causes of autism

{{Main|Heritability of autism}}

{{See also|Missing heritability problem}}

Genetic factors may be the most significant cause of autism. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism. This may be an overestimation, as later twin studies estimate the heritability at between 60 and 90%.{{cite journal | vauthors = Carlsson T, Molander F, Taylor MJ, Jonsson U, Bölte S | title = Early environmental risk factors for neurodevelopmental disorders - a systematic review of twin and sibling studies | journal = Development and Psychopathology | volume = 33 | issue = 4 | pages = 1448–1495 | date = October 2021 | pmid = 32703331 | pmc = 8564717 | doi = 10.1017/S0954579420000620 }} Evidence so far still suggests a strong genetic component, with one of the largest and most recent studies estimating the heritability at 83%.{{cite journal | vauthors = Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A | title = The Heritability of Autism Spectrum Disorder | journal = JAMA | volume = 318 | issue = 12 | pages = 1182–1184 | date = September 2017 | pmid = 28973605 | pmc = 5818813 | doi = 10.1001/jama.2017.12141 }} Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%.{{cite journal | vauthors = Folstein SE, Rosen-Sheidley B | title = Genetics of autism: complex aetiology for a heterogeneous disorder | journal = Nature Reviews. Genetics | volume = 2 | issue = 12 | pages = 943–955 | date = December 2001 | pmid = 11733747 | doi = 10.1038/35103559 | type = Review | s2cid = 9331084 }}

In spite of the strong heritability, most cases of autism occur sporadically with no recent evidence of family history. It has been hypothesized that spontaneous de novo mutations in the sperm or egg contribute to the likelihood of developing autism.{{cite journal | vauthors = Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M | display-authors = 6 | title = Strong association of de novo copy number mutations with autism | journal = Science | volume = 316 | issue = 5823 | pages = 445–449 | date = April 2007 | pmid = 17363630 | pmc = 2993504 | doi = 10.1126/science.1138659 | bibcode = 2007Sci...316..445S }} Additionally, mutations of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) which cause Fragile X Syndrome, the most common cause of intellectual disabilities such as autism, have been linked to the early cessation of reproductive functions of female carriers in the gene. This substantiates the notion that those with autism are more likely to be infertile, weakening the heritability of the disorder.{{Cite journal |last1=Villa |first1=Pedro A. |last2=Lainez |first2=Nancy M. |last3=Jonak |first3=Carrie R. |last4=Berlin |first4=Sarah C. |last5=Ethell |first5=Iryna M. |last6=Coss |first6=Djurdjica |date=2023-02-22 |title=Altered GnRH neuron and ovarian innervation characterize reproductive dysfunction linked to the Fragile X messenger ribonucleoprotein (Fmr1) gene mutation |journal=Frontiers in Endocrinology |language=English |volume=14 |doi=10.3389/fendo.2023.1129534 |doi-access=free |pmid=36909303 |pmc=9992745 |issn=1664-2392}} Also, the likelihood of having a child develop autism generally increases with advancing parental age, and mutations in sperm gradually accumulate throughout a man's life.{{cite journal | vauthors = Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K | display-authors = 6 | title = Rate of de novo mutations and the importance of father's age to disease risk | journal = Nature | volume = 488 | issue = 7412 | pages = 471–475 | date = August 2012 | pmid = 22914163 | pmc = 3548427 | doi = 10.1038/nature11396 | bibcode = 2012Natur.488..471K }}

The first genes to be definitively shown to contribute to risk for autism were found in the early 1990s by researchers looking at gender-specific forms of autism caused by mutations on the X chromosome. An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1 in boys causes fragile X syndrome, and at least 20% of boys with this mutation have behaviors consistent with autism spectrum disorder.{{cite journal | vauthors = Man L, Lekovich J, Rosenwaks Z, Gerhardt J | title = Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations | journal = Frontiers in Molecular Neuroscience | volume = 10 | pages = 290 | date = 2017-09-12 | pmid = 28955201 | pmc = 5600956 | doi = 10.3389/fnmol.2017.00290 | doi-access = free }}{{cite journal | vauthors = Hatton DD, Sideris J, Skinner M, Mankowski J, Bailey DB, Roberts J, Mirrett P | title = Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP | journal = American Journal of Medical Genetics. Part A | volume = 140A | issue = 17 | pages = 1804–1813 | date = September 2006 | pmid = 16700053 | doi = 10.1002/ajmg.a.31286 | s2cid = 11017841 }} Mutations that inactivate the gene MECP2 cause Rett syndrome, which is associated with autistic behaviors in girls, and in boys the mutation is embryonic lethal.{{cite journal | vauthors = Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY | title = Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 | journal = Nature Genetics | volume = 23 | issue = 2 | pages = 185–188 | date = October 1999 | pmid = 10508514 | doi = 10.1038/13810 | s2cid = 3350350 }}

Besides these early examples, the role of de novo mutations in autism first became evident when DNA microarray technologies reached sufficient resolution to allow the detection of copy number variation (CNV) in the human genome.{{cite journal |display-authors=6 |vauthors=Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Månér S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M |date=July 2004 |title=Large-scale copy number polymorphism in the human genome |journal=Science |volume=305 |issue=5683 |pages=525–528 |bibcode=2004Sci...305..525S |doi=10.1126/science.1098918 |pmid=15273396 |s2cid=20357402}}{{cite journal |author-link5=Patricia K. Donahoe |display-authors=6 |vauthors=Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C |date=September 2004 |title=Detection of large-scale variation in the human genome |journal=Nature Genetics |volume=36 |issue=9 |pages=949–951 |doi=10.1038/ng1416 |pmid=15286789 |s2cid=1433674 |doi-access=free}} CNVs are the most common type of structural variation in the genome, consisting of deletions and duplications of DNA that range in size from a kilobase to a few megabases. Microarray analysis has shown that de novo CNVs occur at a significantly higher rate in sporadic cases of autism as compared to the rate in their typically developing siblings and unrelated controls. A series of studies have shown that gene disrupting de novo CNVs occur approximately four times more frequently in autism than in controls and contribute to approximately 5–10% of cases.{{cite journal |display-authors=6 |vauthors=Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW |date=May 2014 |title=Convergence of genes and cellular pathways dysregulated in autism spectrum disorders |journal=American Journal of Human Genetics |volume=94 |issue=5 |pages=677–694 |doi=10.1016/j.ajhg.2014.03.018 |pmc=4067558 |pmid=24768552}}{{cite journal |display-authors=6 |vauthors=Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M |date=June 2011 |title=Rare de novo and transmitted copy-number variation in autistic spectrum disorders |journal=Neuron |volume=70 |issue=5 |pages=886–897 |doi=10.1016/j.neuron.2011.05.015 |pmid=21658582 |s2cid=11132936|doi-access=free }}{{cite journal |display-authors=6 |vauthors=Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Geschwind D, Roeder K, Devlin B, State MW |date=June 2011 |title=Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism |journal=Neuron |volume=70 |issue=5 |pages=863–885 |doi=10.1016/j.neuron.2011.05.002 |pmc=3939065 |pmid=21658581 |author65-link=Kathryn Roeder}} Based on these studies, there are predicted to be 130–234 autism-related CNV loci. The first whole genome sequencing study to comprehensively catalog de novo structural variation at a much higher resolution than DNA microarray studies has shown that the mutation rate is approximately 20% and not elevated in autism compared to sibling controls.{{cite journal |display-authors=6 |vauthors=Brandler WM, Antaki D, Gujral M, Noor A, Rosanio G, Chapman TR, Barrera DJ, Lin GN, Malhotra D, Watts AC, Wong LC, Estabillo JA, Gadomski TE, Hong O, Fajardo KV, Bhandari A, Owen R, Baughn M, Yuan J, Solomon T, Moyzis AG, Maile MS, Sanders SJ, Reiner GE, Vaux KK, Strom CM, Zhang K, Muotri AR, Akshoomoff N, Leal SM, Pierce K, Courchesne E, Iakoucheva LM, Corsello C, Sebat J |date=April 2016 |title=Frequency and Complexity of De Novo Structural Mutation in Autism |journal=American Journal of Human Genetics |volume=98 |issue=4 |pages=667–679 |doi=10.1016/j.ajhg.2016.02.018 |pmc=4833290 |pmid=27018473}} Structural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies.

CNV studies were closely followed by exome sequencing studies, which sequence the 1–2% of the genome that codes for proteins (the "exome"). These studies found that de novo gene inactivating mutations were observed in approximately 20% of individuals with autism, compared to 10% of unaffected siblings, suggesting the etiology of autism is driven by these mutations in around 10% of cases.{{cite journal |display-authors=6 |vauthors=Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M |date=April 2012 |title=De novo gene disruptions in children on the autistic spectrum |journal=Neuron |volume=74 |issue=2 |pages=285–299 |doi=10.1016/j.neuron.2012.04.009 |pmc=3619976 |pmid=22542183}}{{cite journal |display-authors=6 |vauthors=De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD |date=November 2014 |title=Synaptic, transcriptional and chromatin genes disrupted in autism |journal=Nature |volume=515 |issue=7526 |pages=209–215 |bibcode=2014Natur.515..209. |doi=10.1038/nature13772 |pmc=4402723 |pmid=25363760}}{{cite journal |display-authors=6 |vauthors=Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M |date=November 2014 |title=The contribution of de novo coding mutations to autism spectrum disorder |journal=Nature |volume=515 |issue=7526 |pages=216–221 |bibcode=2014Natur.515..216I |doi=10.1038/nature13908 |pmc=4313871 |pmid=25363768}}{{cite journal |display-authors=6 |vauthors=Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ |date=April 2012 |title=Patterns and rates of exonic de novo mutations in autism spectrum disorders |journal=Nature |volume=485 |issue=7397 |pages=242–245 |bibcode=2012Natur.485..242N |doi=10.1038/nature11011 |pmc=3613847 |pmid=22495311}}{{cite journal |display-authors=6 |vauthors=Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW |date=April 2012 |title=De novo mutations revealed by whole-exome sequencing are strongly associated with autism |journal=Nature |volume=485 |issue=7397 |pages=237–241 |bibcode=2012Natur.485..237S |doi=10.1038/nature10945 |pmc=3667984 |pmid=22495306}}{{cite journal |display-authors=6 |vauthors=O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE |date=April 2012 |title=Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |journal=Nature |volume=485 |issue=7397 |pages=246–250 |bibcode=2012Natur.485..246O |doi=10.1038/nature10989 |pmc=3350576 |pmid=22495309}} There are predicted to be 350-450 genes that significantly increase susceptibility to autism when impacted by inactivating de novo mutations.{{cite journal |vauthors=Ronemus M, Iossifov I, Levy D, Wigler M |date=February 2014 |title=The role of de novo mutations in the genetics of autism spectrum disorders |journal=Nature Reviews. Genetics |volume=15 |issue=2 |pages=133–141 |doi=10.1038/nrg3585 |pmid=24430941 |s2cid=9073763}} A further 12% of cases are predicted to be caused by protein altering missense mutations that change an amino acid but do not inactivate a gene. Therefore, approximately 30% of individuals with autism have a spontaneous de novo large CNV that deletes or duplicates genes, or mutation that changes the amino acid code of an individual gene. A further 5–10% of cases have inherited structural variation at loci known to be associated with autism, and these known structural variants may arise de novo in the parents of affected children.

Tens of genes and CNVs have been definitively identified based on the observation of recurrent mutations in different individuals, and suggestive evidence has been found for over 100 others.{{cite journal |vauthors=Betancur C |date=March 2011 |title=Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting |url=https://www.hal.inserm.fr/inserm-00549873/file/Betancur_Brain_Res_2010.pdf |journal=Brain Research |volume=1380 |pages=42–77 |doi=10.1016/j.brainres.2010.11.078 |pmid=21129364 |s2cid=41429306}} The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic locus associated with autism.{{cite web |title=SFARI Gene |url=https://gene.sfari.org/autdb/Welcome.do |url-status=dead |archive-url=https://web.archive.org/web/20160401224329/https://gene.sfari.org/autdb/Welcome.do |archive-date=2016-04-01 |access-date=2016-04-13 |website=SFARI gene}}

These early gene and CNV findings have shown that the cognitive and behavioral features associated with each of the underlying mutations is variable. Each mutation is itself associated with a variety of clinical diagnoses, and can also be found in a small percentage of individuals with no clinical diagnosis.{{cite journal |display-authors=6 |vauthors=Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, Bjornsdottir G, Walters GB, Jonsdottir GA, Doyle OM, Tost H, Grimm O, Kristjansdottir S, Snorrason H, Davidsdottir SR, Gudmundsson LJ, Jonsson GF, Stefansdottir B, Helgadottir I, Haraldsson M, Jonsdottir B, Thygesen JH, Schwarz AJ, Didriksen M, Stensbøl TB, Brammer M, Kapur S, Halldorsson JG, Hreidarsson S, Saemundsen E, Sigurdsson E, Stefansson K |date=January 2014 |title=CNVs conferring risk of autism or schizophrenia affect cognition in controls |journal=Nature |volume=505 |issue=7483 |pages=361–366 |bibcode=2014Natur.505..361S |doi=10.1038/nature12818 |pmid=24352232 |s2cid=3842341 |hdl-access=free |hdl=2336/311615}}{{cite journal |display-authors=6 |vauthors=Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA, Probst FJ, Craigen WJ, Graham BH, Pursley A, Clark G, Lee J, Proud M, Stocco A, Rodriguez DL, Kozel BA, Sparagana S, Roeder ER, McGrew SG, Kurczynski TW, Allison LJ, Amato S, Savage S, Patel A, Stankiewicz P, Beaudet AL, Cheung SW, Lupski JR |date=May 2010 |title=Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size |journal=Journal of Medical Genetics |volume=47 |issue=5 |pages=332–341 |doi=10.1136/jmg.2009.073015 |pmc=3158566 |pmid=19914906}} Thus the genetic disorders that comprise autism are not autism-specific. The mutations themselves are characterized by considerable variability in clinical outcome and typically only a subset of mutation carriers meet criteria for autism. This variable expressivity results in different individuals with the same mutation varying considerably in the severity of their observed particular trait.{{cite journal |vauthors=Brandler WM, Sebat J |date=14 January 2015 |title=From de novo mutations to personalized therapeutic interventions in autism |journal=Annual Review of Medicine |volume=66 |issue=1 |pages=487–507 |doi=10.1146/annurev-med-091113-024550 |pmid=25587659}}

The conclusion of these recent studies of de novo mutation is that the spectrum of autism is breaking up into quanta of individual disorders defined by genetics.

One gene that has been linked to autism is SHANK2.{{cite journal |display-authors=6 |vauthors=Zaslavsky K, Zhang WB, McCready FP, Rodrigues DC, Deneault E, Loo C, Zhao M, Ross PJ, El Hajjar J, Romm A, Thompson T, Piekna A, Wei W, Wang Z, Khattak S, Mufteev M, Pasceri P, Scherer SW, Salter MW, Ellis J |date=April 2019 |title=SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons |journal=Nature Neuroscience |volume=22 |issue=4 |pages=556–564 |doi=10.1038/s41593-019-0365-8 |pmc=6475597 |pmid=30911184}} Mutations in this gene act in a dominant fashion and appear to cause hyperconnectivity between the neurons.

A study conducted on 42,607 autism cases has identified 60 new genes, five of which had a more moderate impact on autistic symptoms. The related gene variants were often inherited from the participant's parents.{{cite journal |author=Columbia University Irving Medical Center |date=September 4, 2022 |title=60 New Genes Linked to Autism Uncovered |url=https://scitechdaily.com/60-new-genes-linked-to-autism-uncovered/amp/ |journal=Nature Genetics |publisher=SciTech Daily |volume=54 |issue=9 |pages=1305–1319 |doi=10.1038/s41588-022-01148-2 |pmc=9470534 |pmid=35982159 |access-date=September 7, 2022}}

{{Main|Epigenetics of autism}}Epigenetic mechanisms may increase the risk of autism. Epigenetic changes occur as a result not of DNA sequence changes but of chromosomal histone modification or modification of the DNA bases. Such modifications are known to be affected by environmental factors, including nutrition, drugs, and mental stress.{{cite book |vauthors=Miyake K, Hirasawa T, Koide T, Kubota T |title=Neurodegenerative Diseases |chapter=Epigenetics in Autism and Other Neurodevelopmental Diseases |series=Advances in Experimental Medicine and Biology |year=2012 |type=Review |volume=724 |pages=91–98 |doi=10.1007/978-1-4614-0653-2_7 |isbn=978-1-4614-0652-5 |pmid=22411236}} Interest has been expressed in imprinted regions on chromosomes 15q and 7q.{{cite journal |vauthors=Schanen NC |date=October 2006 |title=Epigenetics of autism spectrum disorders |journal=Human Molecular Genetics |type=Review |volume=15 Spec No 2 |issue= |pages=R138–R150 |doi=10.1093/hmg/ddl213 |pmid=16987877}}

Most data supports a polygenic, epistatic model, meaning that the disorder is caused by two or more genes and that those genes are interacting in a complex manner. Several genes, between two and fifteen in number, have been identified and could potentially contribute to disease susceptibility.{{cite journal |vauthors=Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M |date=September 1995 |title=Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism |journal=American Journal of Human Genetics |volume=57 |issue=3 |pages=717–726 |pmc=1801262 |pmid=7668301}}{{cite journal |display-authors=6 |vauthors=Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Petersen PB, Pingree C, McMahon W, Wong DL, Cavalli-Sforza LL, Kraemer HC, Myers RM |date=August 1999 |title=A genomic screen of autism: evidence for a multilocus etiology |journal=American Journal of Human Genetics |volume=65 |issue=2 |pages=493–507 |doi=10.1086/302497 |pmc=1377948 |pmid=10417292}} An exact determination of the cause of ASD has yet to be discovered and there probably is not one single genetic cause of any particular set of disorders, leading many researchers to believe that epigenetic mechanisms, such as genomic imprinting or epimutations, may play a major role.{{cite journal |vauthors=Samaco RC, Hogart A, LaSalle JM |date=February 2005 |title=Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 |journal=Human Molecular Genetics |volume=14 |issue=4 |pages=483–492 |doi=10.1093/hmg/ddi045 |pmc=1224722 |pmid=15615769}}{{cite journal |display-authors=6 |vauthors=Jiang YH, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD, Liu Q, Shaffer LG, Schroer RJ, Stockton DW, Spielman RS, Stevenson RE, Beaudet AL |date=November 2004 |title=A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A |journal=American Journal of Medical Genetics. Part A |volume=131 |issue=1 |pages=1–10 |doi=10.1002/ajmg.a.30297 |pmid=15389703 |s2cid=9570482}}

Epigenetic mechanisms can contribute to disease phenotypes. Epigenetic modifications include DNA cytosine methylation and post-translational modifications to histones. These mechanisms contribute to regulating gene expression without changing the sequence of the DNA and may be influenced by exposure to environmental factors and may be heritable from parents. Rett syndrome and Fragile X syndrome (FXS) are single gene disorders related to autism with overlapping symptoms that include deficient neurological development, impaired language and communication, difficulties in social interactions, and stereotyped hand gestures. It is not uncommon for a patient to be diagnosed with both autism and Rett syndrome and/or FXS. Epigenetic regulatory mechanisms play the central role in pathogenesis of these two disorders.{{cite journal |vauthors=Lopez-Rangel E, Lewis ME |date=2006 |title=Further evidence for pigenetic influence of MECP2 in Rett, autism and Angelman's syndromes |journal=Clinical Genetics |volume=69 |issue=1 |pages=23–25 |doi=10.1111/j.1399-0004.2006.00543c.x |s2cid=85160435}}{{cite journal |vauthors=Hagerman RJ, Ono MY, Hagerman PJ |date=September 2005 |title=Recent advances in fragile X: a model for autism and neurodegeneration |journal=Current Opinion in Psychiatry |volume=18 |issue=5 |pages=490–496 |doi=10.1097/01.yco.0000179485.39520.b0 |pmid=16639106 |s2cid=33650811}}

Genomic imprinting may also contribute to the development of autism. Genomic imprinting is another example of epigenetic regulation of gene expression. In this instance, the epigenetic modification(s) causes the offspring to express the maternal copy of a gene or the paternal copy of a gene, but not both. The imprinted gene is silenced through epigenetic mechanisms. Candidate genes and susceptibility alleles for autism are identified using a combination of techniques, including genome-wide and targeted analyses of allele sharing in sib-pairs, using association studies and transmission disequilibrium testing (TDT) of functional and/or positional candidate genes and examination of novel and recurrent cytogenetic aberrations. Results from numerous studies have identified several genomic regions known to be subject to imprinting, candidate genes, and gene-environment interactions. Particularly, chromosomes 15q and 7q appear to be epigenetic hotspots in contributing to autism. Also, genes on the X chromosome may play an important role, as in Rett Syndrome.

An important basis for autism causation is also the over- or underproduction of brain permanent cells (neurons, oligodendrocytes, and astrocytes) by the neural precursor cells during fetal development.{{cite web |author=Rutgers University |date=August 21, 2022 |title=Scientists Discover That Irregular Production of Brain Cells Could Cause Autism |url=https://scitechdaily.com/scientists-discover-that-irregular-production-of-brain-cells-could-cause-autism/amp/ |publisher=SciTech Daily}}

The development of autism is associated with several prenatal risk factors, including advanced age in either parent, diabetes, bleeding, and maternal use of antibiotics and psychiatric drugs during pregnancy.{{cite journal | vauthors = Lee E, Cho J, Kim KY | title = The Association between Autism Spectrum Disorder and Pre- and Postnatal Antibiotic Exposure in Childhood-A Systematic Review with Meta-Analysis | journal = International Journal of Environmental Research and Public Health | volume = 16 | issue = 20 | pages = 4042 | date = October 2019 | pmid = 31652518 | pmc = 6843945 | doi = 10.3390/ijerph16204042 | doi-access = free }}{{cite journal | vauthors = Morales DR, Slattery J, Evans S, Kurz X | title = Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 6 | date = January 2018 | pmid = 29332605 | pmc = 5767968 | doi = 10.1186/s12916-017-0993-3 | doi-access = free }} Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.{{cite journal | vauthors = Roullet FI, Lai JK, Foster JA | title = In utero exposure to valproic acid and autism--a current review of clinical and animal studies | journal = Neurotoxicology and Teratology | volume = 36 | issue = | pages = 47–56 | year = 2013 | pmid = 23395807 | doi = 10.1016/j.ntt.2013.01.004 | bibcode = 2013NTxT...36...47R | type = Review }} If the mother of the child is dealing with autoimmune conditions or disorders while pregnant, it may have an effect on the child's development of autism.{{cite journal | vauthors = Han VX, Patel S, Jones HF, Nielsen TC, Mohammad SS, Hofer MJ, Gold W, Brilot F, Lain SJ, Nassar N, Dale RC | display-authors = 6 | title = Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review | journal = Translational Psychiatry | volume = 11 | issue = 1 | pages = 71 | date = January 2021 | pmid = 33479207 | pmc = 7820474 | doi = 10.1038/s41398-021-01198-w }} All of these factors can cause inflammation or impair immune signaling in one way or another.

Sleep apnea can result in intermittent hypoxia and has been increasing in prevalence due in part to the obesity epidemic. The known maternal risk factors for autism diagnosis in her offspring are similar to the risk factors for sleep apnea. For example, advanced maternal age, maternal obesity, maternal type 2 diabetes and maternal hypertension all increase the risk of autism in her offspring.{{cite journal |vauthors=Xu G, Jing J, Bowers K, Liu B, Bao W |date=April 2014 |title=Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis |journal=Journal of Autism and Developmental Disorders |volume=44 |issue=4 |pages=766–775 |doi=10.1007/s10803-013-1928-2 |pmc=4181720 |pmid=24057131}}{{cite journal |vauthors=Maher GM, O'Keeffe GW, Kearney PM, Kenny LC, Dinan TG, Mattsson M, Khashan AS |date=August 2018 |title=Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis |journal=JAMA Psychiatry |volume=75 |issue=8 |pages=809–819 |doi=10.1001/jamapsychiatry.2018.0854 |pmc=6143097 |pmid=29874359}}{{cite journal |vauthors=Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A |date=May 2012 |title=Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=51 |issue=5 |pages=477–486.e1 |doi=10.1016/j.jaac.2012.02.018 |pmid=22525954}}{{cite journal |vauthors=Wang Y, Tang S, Xu S, Weng S, Liu Z |date=September 2016 |title=Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis |journal=Scientific Reports |volume=6 |pages=34248 |bibcode=2016NatSR...634248W |doi=10.1038/srep34248 |pmc=5043237 |pmid=27687989}} Likewise, these are all known risk factors for sleep apnea.{{cite journal |display-authors=6 |vauthors=Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TG |date=April 2000 |title=Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study |journal=JAMA |volume=283 |issue=14 |pages=1829–1836 |doi=10.1001/jama.283.14.1829 |pmid=10770144}}{{cite journal |vauthors=Muraki I, Wada H, Tanigawa T |date=September 2018 |title=Sleep apnea and type 2 diabetes |journal=Journal of Diabetes Investigation |volume=9 |issue=5 |pages=991–997 |doi=10.1111/jdi.12823 |pmc=6123041 |pmid=29453905 |s2cid=4871197}}{{cite journal |vauthors=Punjabi NM |date=February 2008 |title=The epidemiology of adult obstructive sleep apnea |journal=Proceedings of the American Thoracic Society |volume=5 |issue=2 |pages=136–143 |doi=10.1513/pats.200709-155MG |pmc=2645248 |pmid=18250205}}

One study found that gestational sleep apnea was associated with low reading test scores in children and that this effect may be mediated by an increased risk of the child having sleep apnea themselves.{{cite journal | vauthors = Bin YS, Cistulli PA, Roberts CL, Ford JB | title = Childhood Health and Educational Outcomes Associated With Maternal Sleep Apnea: A Population Record-Linkage Study | journal = Sleep | volume = 40 | issue = 11 | date = November 2017 | pmid = 29029347 | doi = 10.1093/sleep/zsx158 | doi-access = free }} Another study reported low social development scores in 64% of infants born to mothers with sleep apnea compared to 25% of infants born to controls, suggesting sleep apnea in pregnancy may have an effect on offspring neurodevelopment.{{cite journal | vauthors = Tauman R, Zuk L, Uliel-Sibony S, Ascher-Landsberg J, Katsav S, Farber M, Sivan Y, Bassan H | display-authors = 6 | title = The effect of maternal sleep-disordered breathing on the infant's neurodevelopment | journal = American Journal of Obstetrics and Gynecology | volume = 212 | issue = 5 | pages = 656.e1–656.e7 | date = May 2015 | pmid = 25576821 | doi = 10.1016/j.ajog.2015.01.001 }} There was also an increase in the amount of snoring the mothers with sleep apnea reported in their infants when compared to controls. Children with sleep apnea have "hyperactivity, attention problems, aggressivity, lower social competency, poorer communication, and/or diminished adaptive skills".{{cite journal | vauthors = Perfect MM, Archbold K, Goodwin JL, Levine-Donnerstein D, Quan SF | title = Risk of behavioral and adaptive functioning difficulties in youth with previous and current sleep disordered breathing | journal = Sleep | volume = 36 | issue = 4 | pages = 517–525B | date = April 2013 | pmid = 23543901 | pmc = 3595180 | doi = 10.5665/sleep.2536 }} One study found significant improvements in ADHD-like symptoms, aggression, social problems and thought problems in autistic children who underwent adenotonsillectomy for sleep apnea.{{cite journal | vauthors = Murata E, Mohri I, Kato-Nishimura K, Iimura J, Ogawa M, Tachibana M, Ohno Y, Taniike M | display-authors = 6 | title = Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder | journal = Research in Developmental Disabilities | volume = 65 | pages = 127–139 | date = June 2017 | pmid = 28514706 | doi = 10.1016/j.ridd.2017.04.012 | doi-access = free }} Sleep problems in autism have been linked in a study to brain changes, particularly in the hippocampus, though this study does not prove causation.{{cite journal | vauthors = MacDuffie KE, Shen MD, Dager SR, Styner MA, Kim SH, Paterson S, Pandey J, St John T, Elison JT, Wolff JJ, Swanson MR, Botteron KN, Zwaigenbaum L, Piven J, Estes AM | display-authors = 6 | title = Sleep Onset Problems and Subcortical Development in Infants Later Diagnosed With Autism Spectrum Disorder | journal = The American Journal of Psychiatry | volume = 177 | issue = 6 | pages = 518–525 | date = June 2020 | pmid = 32375538 | pmc = 7519575 | doi = 10.1176/appi.ajp.2019.19060666 }} A common presentation of sleep apnea in children with autism is insomnia.{{Cite journal |last1=Santapuram |first1=Pooja |last2=Chen |first2=Heidi |last3=Weitlauf |first3=Amy S. |last4=Ghani |first4=Muhammad Owais A. |last5=Whigham |first5=Amy S. |date=July 2022 |title=Investigating differences in symptomatology and age at diagnosis of obstructive sleep apnea in children with and without autism |url=https://pubmed.ncbi.nlm.nih.gov/35636082/#:~:text=Children%20with%20OSA%20can%20present,in%20children%20with%20both%20conditions. |journal=International Journal of Pediatric Otorhinolaryngology |volume=158 |pages=111191 |doi=10.1016/j.ijporl.2022.111191 |issn=1872-8464 |pmid=35636082}} All known genetic syndromes which are linked to autism have a high prevalence of sleep apnea. The prevalence of sleep apnea in Down's Syndrome is 50% - 100%.{{Cite journal |last1=Maris |first1=Mieke |last2=Verhulst |first2=Stijn |last3=Wojciechowski |first3=Marek |last4=Van de Heyning |first4=Paul |last5=Boudewyns |first5=An |date=2016-03-01 |title=Prevalence of Obstructive Sleep Apnea in Children with Down Syndrome |journal=Sleep |volume=39 |issue=3 |pages=699–704 |doi=10.5665/sleep.5554 |issn=0161-8105 |pmc=4763351 |pmid=26612391}} Sleep problems and OSA in this population have been linked to language development.{{Cite journal |last1=Lee |first1=Ni-Chung |last2=Hsu |first2=Wei-Chung |last3=Chang |first3=Lih-Maan |last4=Chen |first4=Yi-Chen |last5=Huang |first5=Po-Tsang |last6=Chien |first6=Chun-Chin |last7=Chien |first7=Yin-Hsiu |last8=Chen |first8=Chi-Ling |last9=Hwu |first9=Wuh-Liang |last10=Lee |first10=Pei-Lin |date=January 2020 |title=REM sleep and sleep apnea are associated with language function in Down syndrome children: An analysis of a community sample |journal=Journal of the Formosan Medical Association = Taiwan Yi Zhi |volume=119 |issue=1 Pt 3 |pages=516–523 |doi=10.1016/j.jfma.2019.07.015 |issn=0929-6646 |pmid=31378642|doi-access=free }} Since autism manifests in the early developmental period, sleep apnea in Down's Syndrome and other genetic syndromes such as Fragile X start early (at infancy or shortly after), and sleep disturbances alter brain development,{{Cite journal |last1=Lord |first1=Julia S. |last2=Gay |first2=Sean M. |last3=Harper |first3=Kathryn M. |last4=Nikolova |first4=Viktoriya D. |last5=Smith |first5=Kirsten M. |last6=Moy |first6=Sheryl S. |last7=Diering |first7=Graham H. |date=2022-08-29 |title=Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice |journal=Molecular Autism |volume=13 |issue=1 |pages=35 |doi=10.1186/s13229-022-00514-5 |doi-access=free |issn=2040-2392 |pmc=9425965 |pmid=36038911}} it's plausible that some of the neurodevelopmental differences seen in these genetic syndromes are at least partially caused by the effects of untreated sleep apnea.

One hypothesis suggests that prenatal viral infection may contribute to the development of autism. Prenatal exposure to rubella or cytomegalovirus activates the mother's immune response and may greatly increase the risk for autism in mice.{{cite journal | vauthors = Libbey JE, Sweeten TL, McMahon WM, Fujinami RS | title = Autistic disorder and viral infections | journal = Journal of Neurovirology | volume = 11 | issue = 1 | pages = 1–10 | date = February 2005 | pmid = 15804954 | doi = 10.1080/13550280590900553 | type = Review | s2cid = 9962647 }} Congenital rubella syndrome is the most convincing environmental cause of autism.{{cite journal | vauthors = Mendelsohn NJ, Schaefer GB | title = Genetic evaluation of autism | journal = Seminars in Pediatric Neurology | volume = 15 | issue = 1 | pages = 27–31 | date = March 2008 | pmid = 18342258 | doi = 10.1016/j.spen.2008.01.005 | type = Review }}{{How|date=January 2025}} Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for psychiatric disorders of presumed neurodevelopmental origin, notably schizophrenia.{{cite journal | vauthors = Meyer U, Yee BK, Feldon J | title = The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? | journal = The Neuroscientist | volume = 13 | issue = 3 | pages = 241–256 | date = June 2007 | pmid = 17519367 | doi = 10.1177/1073858406296401 | type = Review | s2cid = 26096561 }}

A 2021 meta-analysis of 36 studies suggested a relationship between mothers recalling an infection during pregnancy and having children with autism.{{Cite journal |last1=Tioleco |first1=Nina |last2=Silberman |first2=Anna E. |last3=Stratigos |first3=Katharine |last4=Banerjee-Basu |first4=Sharmila |last5=Spann |first5=Marisa N. |last6=Whitaker |first6=Agnes H. |last7=Turner |first7=J. Blake |date=2021 |title=Prenatal maternal infection and risk for autism in offspring: A meta-analysis |journal=Autism Research |language=en |volume=14 |issue=6 |pages=1296–1316 |doi=10.1002/aur.2499 |issn=1939-3792 |doi-access=free|pmid=33720503 }}

Teratogens are environmental agents that cause birth defects. Some agents that are theorized to cause birth defects have also been suggested as potential autism risk factors, although there is little to no scientific evidence to back such claims. These include exposure of the embryo to valproic acid, paracetamol,{{cite journal | vauthors = Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, García-Esteban R, Galán IR, Tardón A, Rodríguez-Bernal CL, Iñiguez C, Andiarena A, Santa-Marina L, Sunyer J | display-authors = 6 | title = Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms | journal = International Journal of Epidemiology | volume = 45 | issue = 6 | pages = 1987–1996 | date = December 2016 | pmid = 27353198 | doi = 10.1093/ije/dyw115 | doi-access = free | hdl = 10651/42938 | hdl-access = free }} thalidomide or misoprostol.{{cite journal | vauthors = Dufour-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, Andres CR | title = Fetal exposure to teratogens: evidence of genes involved in autism | journal = Neuroscience and Biobehavioral Reviews | volume = 35 | issue = 5 | pages = 1254–1265 | date = April 2011 | pmid = 21195109 | doi = 10.1016/j.neubiorev.2010.12.013 | type = Review | s2cid = 5180756 }} These cases are rare.{{cite journal | vauthors = Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C | title = Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review | journal = International Journal of Developmental Neuroscience | volume = 23 | issue = 2–3 | pages = 201–219 | year = 2005 | pmid = 15749246 | doi = 10.1016/j.ijdevneu.2004.06.007 |s2cid=14248227}} Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects. All known teratogens appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, it is strong evidence that autism arises very early in development.

A small significant link was shown to exist between prenatal exposure to airborne pollutants and autism risk. This finding was not consistent across studies, and exposure to pollutants was measured indirectly.

Maternal inflammatory and autoimmune diseases can damage embryonic and fetal tissues, aggravating a genetic problem or damaging the nervous system.{{cite journal | vauthors = Samsam M, Ahangari R, Naser SA | title = Pathophysiology of autism spectrum disorders: revisiting gastrointestinal involvement and immune imbalance | journal = World Journal of Gastroenterology |volume=20 | issue = 29 | pages = 9942–9951 | date = August 2014 | pmid = 25110424 | pmc = 4123375 | doi = 10.3748/wjg.v20.i29.9942 | type = Review | doi-access = free }}

Thyroid problems that lead to thyroxine deficiency in the mother in weeks 8–12 of pregnancy have been postulated to produce changes in the fetal brain leading to autism. Thyroxine deficiencies can be caused by inadequate iodine in the diet, and by environmental agents that interfere with iodine uptake or act against thyroid hormones. Possible environmental agents include flavonoids in food, tobacco smoke, and most herbicides. This hypothesis has not been tested.{{cite journal |vauthors=Román GC |date=November 2007 |title=Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents |journal=Journal of the Neurological Sciences |type=Review |volume=262 |issue=1–2 |pages=15–26 |doi=10.1016/j.jns.2007.06.023 |pmid=17651757 |s2cid=31805494}}

Diabetes in the mother during pregnancy is a significant risk factor for autism; a 2009 meta-analysis found that gestational diabetes was associated with a twofold increased risk. A 2014 review also found that maternal diabetes was significantly associated with an increased risk of autism. Although diabetes causes metabolic and hormonal abnormalities and oxidative stress, no biological mechanism is known for the association between gestational diabetes and autism risk.{{cite journal |vauthors=Gardener H, Spiegelman D, Buka SL |date=July 2009 |title=Prenatal risk factors for autism: comprehensive meta-analysis |journal=The British Journal of Psychiatry |type=Review, meta-analysis |volume=195 |issue=1 |pages=7–14 |doi=10.1192/bjp.bp.108.051672 |pmc=3712619 |pmid=19567888}}

Maternal diagnoses of polycystic ovary syndrome was found to associated with higher risk of autism.{{cite journal | vauthors = Katsigianni M, Karageorgiou V, Lambrinoudaki I, Siristatidis C | title = Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis | journal = Molecular Psychiatry | volume = 24 | issue = 12 | pages = 1787–1797 | date = December 2019 | pmid = 30867561 | doi = 10.1038/s41380-019-0398-0 | s2cid = 76660638 | eissn = 1476-5578 }}

Maternal obesity during pregnancy may also increase the risk of autism, although further study is needed.{{cite journal |vauthors=Li YM, Ou JJ, Liu L, Zhang D, Zhao JP, Tang SY |date=January 2016 |title=Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis |url=https://zenodo.org/record/845351 |journal=Journal of Autism and Developmental Disorders |volume=46 |issue=1 |pages=95–102 |doi=10.1007/s10803-015-2549-8 |pmid=26254893 |s2cid=26406333}}

Maternal malnutrition during preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is associated with autism, in both term and preterm infants.{{cite journal |vauthors=Vohr BR, Poggi Davis E, Wanke CA, Krebs NF |date=April 2017 |title=Neurodevelopment: The Impact of Nutrition and Inflammation During Preconception and Pregnancy in Low-Resource Settings |journal=Pediatrics |type=Review |volume=139 |issue=Suppl 1 |pages=S38–S49 |doi=10.1542/peds.2016-2828F |pmid=28562247 |s2cid=28637473 |doi-access=free}}

It has been hypothesized that folic acid taken during pregnancy could play a role in reducing cases of autism by modulating gene expression through an epigenetic mechanism. This hypothesis is supported by multiple studies.{{cite journal | vauthors = Lyall K, Schmidt RJ, Hertz-Picciotto I | title = Maternal lifestyle and environmental risk factors for autism spectrum disorders | journal = International Journal of Epidemiology | volume = 43 | issue = 2 | pages = 443–464 | date = April 2014 | pmid = 24518932 | pmc = 3997376 | doi = 10.1093/ije/dyt282 }}

Prenatal stress, consisting of exposure to life events or environmental factors that distress an expectant mother, has been hypothesized to contribute to autism, possibly as part of a gene-environment interaction. Autism has been reported to be associated with prenatal stress both with retrospective studies that examined stressors such as job loss and family discord, and with natural experiments involving prenatal exposure to storms; animal studies have reported that prenatal stress can disrupt brain development and produce behaviors resembling symptoms of autism.{{cite journal | vauthors = Kinney DK, Munir KM, Crowley DJ, Miller AM | title = Prenatal stress and risk for autism | journal = Neuroscience and Biobehavioral Reviews | volume = 32 | issue = 8 | pages = 1519–1532 | date = October 2008 | pmid = 18598714 | pmc = 2632594 | doi = 10.1016/j.neubiorev.2008.06.004 | type = Review }} Other studies cast doubt on this association, notably population based studies in England and Sweden finding no link between stressful life events and autism.{{cite journal | vauthors = Rai D, Golding J, Magnusson C, Steer C, Lewis G, Dalman C | title = Prenatal and early life exposure to stressful life events and risk of autism spectrum disorders: population-based studies in Sweden and England | journal = PLOS ONE | volume = 7 | issue = 6 | pages = e38893 | year = 2012 | pmid = 22719977 | pmc = 3374800 | doi = 10.1371/journal.pone.0038893 | doi-access = free | bibcode = 2012PLoSO...738893R }}

The fetal testosterone theory hypothesizes that higher levels of testosterone in the amniotic fluid of mothers pushes brain development towards improved ability to see patterns and analyze complex systems while diminishing communication and empathy, emphasizing "male" traits over "female", or in E-S theory terminology, emphasizing "systemizing" over "empathizing". One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism.Fetal testosterone and autistic traits:

• {{cite book | veditors = Zimmerman AW | vauthors = Auyeung B, Baron-Cohen S | title = Autism | chapter = A Role for Fetal Testosterone in Human Sex Differences | date = 2008 |doi=10.1007/978-1-60327-489-0_8 |isbn=978-1-60327-488-3 |pages=185–208 |publisher=Humana }}
• {{cite journal | vauthors = Manson JE | title = Prenatal exposure to sex steroid hormones and behavioral/cognitive outcomes | journal = Metabolism | volume = 57 | issue = Suppl 2 | pages = S16–S21 | date = October 2008 | pmid = 18803959 | doi = 10.1016/j.metabol.2008.07.010 | type = Review }}

Based in part on animal studies, diagnostic ultrasounds administered during pregnancy have been hypothesized to increase the child's risk of autism. This hypothesis is not supported by independently published research, and examination of children whose mothers received an ultrasound has failed to find evidence of harmful effects.{{cite journal | vauthors = Abramowicz JS | title = Ultrasound and autism: association, link, or coincidence? | journal = Journal of Ultrasound in Medicine | volume = 31 | issue = 8 | pages = 1261–1269 | date = August 2012 | pmid = 22837291 | doi = 10.7863/jum.2012.31.8.1261 | type = Review | s2cid = 36234852 }}

Some research suggests that maternal exposure to selective serotonin reuptake inhibitors during pregnancy is associated with an increased risk of autism, but it remains unclear whether there is a causal link between the two.{{cite journal | vauthors = Man KK, Tong HH, Wong LY, Chan EW, Simonoff E, Wong IC | title = Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies | journal = Neuroscience and Biobehavioral Reviews | volume = 49 | pages = 82–89 | date = February 2015 | pmid = 25498856 | doi = 10.1016/j.neubiorev.2014.11.020 | s2cid = 8862487 | hdl = 10722/207262 | hdl-access = free }} There is evidence, for example, that this association may be an artifact of confounding by maternal mental illness.{{cite journal | vauthors = Brown HK, Hussain-Shamsy N, Lunsky Y, Dennis CE, Vigod SN | title = The Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Systematic Review and Meta-Analysis | journal = The Journal of Clinical Psychiatry | volume = 78 | issue = 1 | pages = e48–e58 | date = January 2017 | pmid = 28129495 | doi = 10.4088/JCP.15r10194 }}

Paracetamol (acetaminophen) use during pregnancy has been suggested as a possible risk factor for autism. A large prospective review of 2,480,797 children published in JAMA Pediatrics in April 2024 found "acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis".{{cite journal |last1=Ahlqvist |first1=Viktor H. |last2=Sjöqvist |first2=Hugo |last3=Dalman |first3=Christina |last4=Karlsson |first4=Håkan |last5=Stephansson |first5=Olof |last6=Johansson |first6=Stefan |last7=Magnusson |first7=Cecilia |last8=Gardner |first8=Renee M. |last9=Lee |first9=Brian K. |date=2024 |title=Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability |journal=JAMA |volume=331 |issue=14 |pages=1205–1214 |doi=10.1001/jama.2024.3172 |pmc=11004836 |pmid=38592388}}

A meta-analysis published in 2024 concluded that "evidence does not support that maternal alcohol consumption during pregnancy is independently associated with autism spectrum disorders in offspring".{{Cite journal |last1=Luo |first1=Zhengjie |last2=Yang |first2=Chunqiang |last3=Cai |first3=Tingting |last4=Li |first4=Jing |last5=Liu |first5=Yanru |last6=Li |first6=Binbin |last7=Zhang |first7=Xiaoming |date=2024 |title=Maternal Alcohol Consumption During Pregnancy and Autism Spectrum Disorder in Offspring: a Meta-analysis |url=https://link.springer.com/10.1007/s40489-022-00336-4 |journal=Review Journal of Autism and Developmental Disorders |language=en |volume=11 |issue=2 |pages=265–274 |doi=10.1007/s40489-022-00336-4 |issn=2195-7177 |url-access=subscription}}

Autism is associated with some perinatal and obstetric conditions. Infants that are born pre-term often have various neurodevelopmental impairments related to motor skills, cognition, receptive and expressive language, and socio-emotional capabilities.{{cite journal | vauthors = Rogers CE, Lean RE, Wheelock MD, Smyser CD | title = Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children | journal = Journal of Neurodevelopmental Disorders | volume = 10 | issue = 1 | pages = 38 | date = December 2018 | pmid = 30541449 | pmc = 6291944 | doi = 10.1186/s11689-018-9253-x | eissn = 1866-1955 | doi-access = free }} Pre-term infants are also at a higher risk of having various neurodevelopmental disorders such as cerebral palsy and autism, as well as psychiatric disorders related to attention, anxiety, and impaired social communication. It has also been proposed that the functions of the hypothalamic-pituitary-adrenal axis and brain connectivity in pre-term infants may be affected by NICU-related stress resulting in deficits in emotional regulation and socio-emotional capabilities. A 2019 analysis of perinatal and neonatal risk factors found that autism was associated with abnormal fetal positioning, umbilical cord complications, low 5-minute Apgar score, low birth weight and gestation duration, fetal distress, meconium aspiration syndrome, trauma or injury during birth, maternal hemorrhaging, multiple birth, feeding disorders, neonatal anemia, birth defects/malformation, incompatibility with maternal blood type, and jaundice/hyperbilirubinemia. These associations do not denote a causal relationship for any individual factor.{{cite journal | vauthors = Gardener H, Spiegelman D, Buka SL | title = Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis | journal = Pediatrics | volume = 128 | issue = 2 | pages = 344–355 | date = August 2011 | pmid = 21746727 | pmc = 3387855 | doi = 10.1542/peds.2010-1036 }} There is growing evidence that perinatal exposure to air pollution may be a risk factor for autism, although this evidence has methodological limitations, including a small number of studies and failure to control for potential confounding factors.{{cite journal | vauthors = Weisskopf MG, Kioumourtzoglou MA, Roberts AL | title = Air Pollution and Autism Spectrum Disorders: Causal or Confounded? | journal = Current Environmental Health Reports | volume = 2 | issue = 4 | pages = 430–439 | date = December 2015 | pmid = 26399256 | pmc = 4737505 | doi = 10.1007/s40572-015-0073-9 | bibcode = 2015CEHR....2..430W }}{{cite journal | vauthors = Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ | title = Childhood autism spectrum disorders and exposure to nitrogen dioxide, and particulate matter air pollution: A review and meta-analysis | journal = Environmental Research | volume = 151 | issue = | pages = 763–776 | date = November 2016 | pmid = 27609410 | pmc = | doi = 10.1016/j.envres.2016.07.030 | bibcode = 2016ER....151..763F }} A few studies have found an association between autism and frequent use of acetaminophen (e.g. Tylenol, Paracetamol) by the mother during pregnancy.{{cite journal | vauthors = Parker W, Hornik CD, Bilbo S, Holzknecht ZE, Gentry L, Rao R, Lin SS, Herbert MR, Nevison CD | display-authors = 6 | title = The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism | journal = The Journal of International Medical Research | volume = 45 | issue = 2 | pages = 407–438 | date = April 2017 | pmid = 28415925 | pmc = 5536672 | doi = 10.1177/0300060517693423 }}{{cite journal | vauthors = Borchers A, Pieler T | title = Programming pluripotent precursor cells derived from Xenopus embryos to generate specific tissues and organs | journal = Genes | volume = 1 | issue = 3 | pages = 413–426 | date = November 2010 | pmid = 24710095 | doi = 10.3390/e14112227 | pmc = 3966229 | bibcode = 2012Entrp..14.2227S | doi-access = free }} This association does not necessarily demonstrate a causal relationship.

A wide variety of postnatal contributors to autism have been proposed, including gastrointestinal or immune system abnormalities, allergies, and exposure of children to drugs, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies.{{cite journal |vauthors=Rutter M |date=January 2005 |title=Incidence of autism spectrum disorders: changes over time and their meaning |journal=Acta Paediatrica |type=Review |volume=94 |issue=1 |pages=2–15 |doi=10.1111/j.1651-2227.2005.tb01779.x |pmid=15858952 |s2cid=79259285 |authorlink=Michael Rutter}}

This theory hypothesizes that an early developmental failure involving the amygdala cascades on the development of cortical areas that mediate social perception in the visual domain. The fusiform face area of the ventral stream is implicated. The idea is that it is involved in social knowledge and social cognition, and that the deficits in this network are instrumental in causing autism.{{cite journal | vauthors = Schultz RT | title = Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area | journal = International Journal of Developmental Neuroscience | volume = 23 | issue = 2–3 | pages = 125–141 | year = 2005 | pmid = 15749240 | doi = 10.1016/j.ijdevneu.2004.12.012 | type = Review | s2cid = 17078137 }}

This theory hypothesizes that autoantibodies that target the brain or elements of brain metabolism may cause or exacerbate autism. It is related to the maternal infection theory, except that it postulates that the effect is caused by the individual's own antibodies, possibly due to an environmental trigger after birth. It is also related to several other hypothesized causes; for example, viral infection has been hypothesized to cause autism via an autoimmune mechanism.{{cite journal | vauthors = Ashwood P, Van de Water J | title = Is autism an autoimmune disease? | journal = Autoimmunity Reviews | volume = 3 | issue = 7–8 | pages = 557–562 | date = November 2004 | pmid = 15546805 | doi = 10.1016/j.autrev.2004.07.036 | type = Review }}

Interactions between the immune system and the nervous system begin early during embryogenesis, and successful neurodevelopment depends on a balanced immune response. It is possible that aberrant immune activity during critical periods of neurodevelopment is part of the mechanism of some forms of autism.{{cite journal | vauthors = Ashwood P, Wills S, Van de Water J | title = The immune response in autism: a new frontier for autism research | journal = Journal of Leukocyte Biology | volume = 80 | issue = 1 | pages = 1–15 | date = July 2006 | pmid = 16698940 | doi = 10.1189/jlb.1205707 | type = Review | s2cid = 17531542 | doi-access = free }} A small percentage of autism cases are associated with infection, usually before birth. Results from immune studies have been contradictory. Some abnormalities have been found in specific subgroups, and some of these have been replicated. It is not known whether these abnormalities are relevant to the pathology of autism, for example, by infection or autoimmunity, or whether they are secondary to the disease processes.{{cite journal |journal=Res Autism Spectr Disord |volume=3 |issue=4 |year=2009 |pages=840–860 |doi=10.1016/j.rasd.2009.01.007 | vauthors = Stigler KA, Sweeten TL, Posey DJ, McDougle CJ |title=Autism and immune factors: a comprehensive review |type=Review}} As autoantibodies are found in diseases other than autism, and are not always present in autism,{{cite journal | vauthors = Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J | title = Autoantibodies in autism spectrum disorders (ASD) | journal = Annals of the New York Academy of Sciences | volume = 1107 | issue = 1 | pages = 79–91 | date = June 2007 | pmid = 17804535 | doi = 10.1196/annals.1381.009 | type = Review | s2cid = 24708891 | bibcode = 2007NYASA1107...79W }} the relationship between immune disturbances and autism remains unclear and controversial.{{cite journal | vauthors = Schmitz C, Rezaie P | title = The neuropathology of autism: where do we stand? | journal = Neuropathology and Applied Neurobiology | volume = 34 | issue = 1 | pages = 4–11 | date = February 2008 | pmid = 17971078 | doi = 10.1111/j.1365-2990.2007.00872.x | type = Review | s2cid = 23551620 }} A 2015 systematic review and meta-analysis found that children with a family history of autoimmune diseases were at a greater risk of autism compared to children without such a history.{{cite journal | vauthors = Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, Mao P | title = Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis | journal = Neuroscience and Biobehavioral Reviews | volume = 55 | pages = 322–332 | date = August 2015 | pmid = 25981892 | doi = 10.1016/j.neubiorev.2015.05.004 | s2cid = 42029820 }}

When an underlying maternal autoimmune disease is present, antibodies circulating to the fetus could contribute to the development of autism spectrum disorders.{{cite journal | vauthors = Fox E, Amaral D, Van de Water J | title = Maternal and fetal antibrain antibodies in development and disease | journal = Developmental Neurobiology | volume = 72 | issue = 10 | pages = 1327–1334 | date = October 2012 | pmid = 22911883 | pmc = 3478666 | doi = 10.1002/dneu.22052 | type = Review }}

Gastrointestinal problems are one of the most commonly associated medical disorders in people with autism.{{cite journal |vauthors=Israelyan N, Margolis KG |date=June 2018 |title=Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders |journal=Pharmacological Research |type=Review |volume=132 |pages=1–6 |doi=10.1016/j.phrs.2018.03.020 |pmc=6368356 |pmid=29614380}} These are linked to greater social impairment, irritability, behavior and sleep problems, language impairments and mood changes, so the theory that they are an overlap syndrome has been postulated.{{cite journal |vauthors=Wasilewska J, Klukowski M |year=2015 |title=Gastrointestinal symptoms and autism spectrum disorder: links and risks - a possible new overlap syndrome |journal=Pediatric Health, Medicine and Therapeutics |type=Review |volume=6 |pages=153–166 |doi=10.2147/PHMT.S85717 |pmc=5683266 |pmid=29388597 |doi-access=free }} Studies indicate that gastrointestinal inflammation, food allergies, gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity, dysautonomia and gastroesophageal reflux are the mechanisms that possibly link both.

A 2016 review concludes that enteric nervous system abnormalities might play a role in several neurological disorders, including autism. Neural connections and the immune system are a pathway that may allow diseases originated in the intestine to spread to the brain.{{cite journal |vauthors=Rao M, Gershon MD |date=September 2016 |title=The bowel and beyond: the enteric nervous system in neurological disorders |journal=Nature Reviews. Gastroenterology & Hepatology |type=Review |volume=13 |issue=9 |pages=517–528 |doi=10.1038/nrgastro.2016.107 |pmc=5005185 |pmid=27435372}} A 2018 review suggests that the frequent association of gastrointestinal disorders and autism is due to abnormalities of the gut–brain axis.

The "leaky gut syndrome" hypothesis developed by Andrew Wakefield, known for his fraudulent study on another cause of autism, is popular among parents of children with autism.{{cite journal | title = Retraction--Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children | journal = Lancet | volume = 375 | issue = 9713 | pages = 445 | date = February 2010 | pmid = 20137807 | doi = 10.1016/s0140-6736(10)60175-4 | s2cid = 26364726 | vauthors = ((The Editors of The Lancet)) }}{{cite journal | vauthors = Bezawada N, Phang TH, Hold GL, Hansen R | title = Autism Spectrum Disorder and the Gut Microbiota in Children: A Systematic Review | journal = Annals of Nutrition & Metabolism | volume = 76 | issue = 1 | pages = 16–29 | date = 2020 | pmid = 31982866 | doi = 10.1159/000505363 | s2cid = 210922352 | eissn = 1421-9697 | doi-access = free }}{{cite journal | vauthors = Almeida C, Oliveira R, Soares R, Barata P | title = Influence of gut microbiota dysbiosis on brain function: a systematic review | journal = Porto Biomedical Journal | volume = 5 | issue = 2 | page = 1 | date = 2020 | pmid = 33299942 | pmc = 7722401 | doi = 10.1097/j.pbj.0000000000000059 | eissn = 2444-8672 }} It is based on the idea that defects in the intestinal barrier produce an excessive increase in intestinal permeability, allowing substances present in the intestine (including bacteria, environmental toxins, and food antigens) to pass into the blood. The data supporting this theory are limited and contradictory, since both increased intestinal permeability and normal permeability have been documented in people with autism. Studies with mice provide some support to this theory and suggest the importance of intestinal flora, demonstrating that the normalization of the intestinal barrier was associated with an improvement in some of the autism-like behaviors. Studies on subgroups of people with autism showed the presence of high plasma levels of zonulin, a protein that regulates permeability opening the "pores" of the intestinal wall, as well as intestinal dysbiosis (reduced levels of Bifidobacteria and increased abundance of Akkermansia muciniphila, Escherichia coli, Clostridia and Candida fungi that promote the production of proinflammatory cytokines, all of which produces excessive intestinal permeability.{{cite journal | vauthors = Azhari A, Azizan F, Esposito G | title = A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder | journal = Developmental Psychobiology | volume = 61 | issue = 5 | pages = 752–771 | date = July 2019 | pmid = 30523646 | doi = 10.1002/dev.21803 | type = Systematic Review | s2cid = 54523742 | hdl = 10220/49107 | hdl-access = free }} This allows passage of bacterial endotoxins from the gut into the bloodstream, stimulating liver cells to secrete tumor necrosis factor alpha (TNFα), which modulates blood–brain barrier permeability. Studies on ASD people showed that TNFα cascades produce proinflammatory cytokines, leading to peripheral inflammation and activation of microglia in the brain, which indicates neuroinflammation. In addition, neuroactive opioid peptides from digested foods have been shown to leak into the bloodstream and permeate the blood–brain barrier, influencing neural cells and causing autistic symptoms. (See Endogenous opiate precursor theory)

After a preliminary 1998 study of three children with autism treated with secretin infusion reported improved GI function and dramatic improvement in behavior, many parents sought secretin treatment and a black market for the hormone developed quickly.{{cite journal |vauthors=Johnson TW |year=2006 |title=Dietary considerations in autism: identifying a reasonable approach |journal=Top Clin Nutr |volume=21 |issue=3 |pages=212–225 |doi=10.1097/00008486-200607000-00008 |s2cid=76326593}} Later studies found secretin clearly ineffective in treating autism.{{cite journal |vauthors=Krishnaswami S, McPheeters ML, Veenstra-Vanderweele J |date=May 2011 |title=A systematic review of secretin for children with autism spectrum disorders |journal=Pediatrics |type=Review |volume=127 |issue=5 |pages=e1322–e1325 |doi=10.1542/peds.2011-0428 |pmc=3387870 |pmid=21464196}}

{{Main|Opioid excess theory}}In 1979, a possible association between autism and opiate was proposed, it was noted that injecting small amounts of opiates into young laboratory animals resulted in symptoms similar to those seen in autistic children.{{cite journal |vauthors=Panksepp J |year=1979 |title=A neurochemical theory of autism |url= |journal=Trends in Neurosciences |volume=2 |issue= |pages=174–177 |doi=10.1016/0166-2236(79)90071-7 |s2cid=54373822}} The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by Kalle Reichelt in 1991.{{cite journal |vauthors=Millward C, Ferriter M, Calver S, Connell-Jones G |date=April 2008 |title=Gluten- and casein-free diets for autistic spectrum disorder |journal=The Cochrane Database of Systematic Reviews |type=Review |issue=2 |pages=CD003498 |doi=10.1002/14651858.CD003498.pub3 |pmc=4164915 |pmid=18425890}}

Opiate theory hypothesizes that autism is the result of a metabolic disorder in which opioid peptides gliadorphin (aka gluteomorphin) and Casomorphin, produced through metabolism of gluten (present in wheat and related cereals) and casein (present in dairy products), pass through an abnormally permeable intestinal wall and then proceed to exert an effect on neurotransmission through binding with opioid receptors. It has been postulated that the resulting excess of opioids affects brain maturation and causes autistic symptoms including: behavioral difficulties, attention problems, and alterations in communicative capacity and social and cognitive functioning.{{cite journal |vauthors=Shattock P, Whiteley P |date=April 2002 |title=Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention |journal=Expert Opinion on Therapeutic Targets |type=Review |volume=6 |issue=2 |pages=175–183 |doi=10.1517/14728222.6.2.175 |pmid=12223079 |s2cid=40904799}}

Although high levels of these opioids are eliminated in the urine, it has been suggested that a small part of them cross into the brain causing interference of signal transmission and disruption of normal activity. Three studies have reported that urine samples of people with autism show an increased 24-hour peptide excretion. A study with a control group found no appreciable differences in opioid levels in urine samples of people with autism compared to controls. Two studies showed an increased opioid levels in cerebrospinal fluid of people with autism.

The theory further states that removing opiate precursors from a child's diet may allow time for these behaviors to cease, and neurological development in very young children to resume normally.{{cite journal | vauthors = Christison GW, Ivany K | title = Elimination diets in autism spectrum disorders: any wheat amidst the chaff? | journal = Journal of Developmental and Behavioral Pediatrics | volume = 27 | issue = 2 Suppl | pages = S162–S171 | date = April 2006 | pmid = 16685183 | doi = 10.1097/00004703-200604002-00015 }} As of 2021, reliable studies have not demonstrated the benefit of gluten-free diets in the treatment of autism.{{cite journal | vauthors = Aranburu E, Matias S, Simón E, Larretxi I, Martínez O, Bustamante MÁ, Fernández-Gil MD, Miranda J | display-authors = 6 | title = Gluten and FODMAPs Relationship with Mental Disorders: Systematic Review | journal = Nutrients | volume = 13 | issue = 6 | pages = 1894 | date = May 2021 | pmid = 34072914 | pmc = 8228761 | doi = 10.3390/nu13061894 | doi-access = free }} In the subset of people who have gluten sensitivity there is limited evidence that suggests that a gluten-free diet may improve some autistic behaviors.

There have been multiple attempts to uncover a link between various nutritional deficiencies such as vitamin D and folate and autism risk.{{cite journal | vauthors = Modabbernia A, Velthorst E, Reichenberg A | title = Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses | journal = Molecular Autism | volume = 8 | issue = 1 | pages = 13 | date = 2017-03-17 | pmid = 28331572 | pmc = 5356236 | doi = 10.1186/s13229-017-0121-4 | doi-access = free }} Although there have been many studies on the role of vitamin D in the development of autism, the majority of them are limited by their inability to assess the deficiency prior to an autism diagnosis. A meta-analysis on the association between vitamin D and autism found that individuals with autism had significantly low levels of serum 25-hydroxy vitamin D than those without autism. Another analysis showed significant differences in levels of zinc between individuals with and without autism. Although studies showed significant differences protein intake and calcium in individuals with autism, the results were limited by their imprecision, inconsistency, and indirect nature. Additionally, low levels of 5-methyltetrahydrofolate (5-MTHF) in the brain can result in cerebral folate deficiency (CFD) which has been shown to be associated with autism.{{cite journal | vauthors = Rossignol DA, Frye RE | title = Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis | journal = Journal of Personalized Medicine | volume = 11 | issue = 11 | pages = 1141 | date = November 2021 | pmid = 34834493 | pmc = 8622150 | doi = 10.3390/jpm11111141 | doi-access = free }}

Multiple studies have attempted to study the relationship between toxic exposure and autism, despite limitations related to the measurement of toxic exposure the methods for which were often indirect and cross-sectional. Systematic reviews have been conducted for numerous toxins including air pollution, thimerosal, inorganic mercury, and levels of heavy metals in hair, nails, and bodily fluids.

Environmental exposure to inorganic mercury may be associated with higher autism risk, with high levels of mercury in the body being a valid disease-causing agent for autism.{{cite journal | vauthors = Jafari Mohammadabadi H, Rahmatian A, Sayehmiri F, Rafiei M | title = The Relationship Between the Level of Copper, Lead, Mercury and Autism Disorders: A Meta-Analysis | journal = Pediatric Health, Medicine and Therapeutics | volume = 11 | pages = 369–378 | date = 2020-09-21 | pmid = 33061742 | pmc = 7519826 | doi = 10.2147/PHMT.S210042 | doi-access = free }}

Significant evidence has not been found of an association between autism and the concentration of copper, cadmium, selenium, and chromium in the hair, nails, and bodily fluids.{{cite journal | vauthors = Islam GM, Rahman MM, Hasan MI, Tadesse AW, Hamadani JD, Hamer DH | title = Hair, serum and urine chromium levels in children with cognitive defects: A systematic review and meta-analysis of case control studies | journal = Chemosphere | volume = 291 | issue = Pt 2 | pages = 133017 | date = March 2022 | pmid = 34813844 | pmc = 8792285 | doi = 10.1016/j.chemosphere.2021.133017 | bibcode = 2022Chmsp.29133017I | eissn = 1879-1298 }} Levels of lead were found to be significantly higher in individuals with autism. The precision and consistency of results were not maintained across studies and were influenced by an outlier study. The atypical eating behaviors of autistic children, along with habitual mouthing and pica, make it hard to determine whether increased lead levels are a cause or a consequence of autism.{{cite journal | vauthors = Zafeiriou DI, Ververi A, Vargiami E | title = Childhood autism and associated comorbidities | journal = Brain & Development | volume = 29 | issue = 5 | pages = 257–272 | date = June 2007 | pmid = 17084999 | doi = 10.1016/j.braindev.2006.09.003 | type = Review | s2cid = 16386209 }}

This theory hypothesizes that autistic behaviors depend at least in part on a developmental dysregulation that results in impaired function of the locus coeruleus–noradrenergic (LC-NA) system. The LC-NA system is heavily involved in arousal and attention; for example, it is related to the brain's acquisition and use of environmental cues.{{cite journal | vauthors = Mehler MF, Purpura DP | title = Autism, fever, epigenetics and the locus coeruleus | journal = Brain Research Reviews | volume = 59 | issue = 2 | pages = 388–392 | date = March 2009 | pmid = 19059284 | pmc = 2668953 | doi = 10.1016/j.brainresrev.2008.11.001 | type = Review }} For a lay summary, see {{cite magazine | vauthors = Kluger J | title = Why Fever Helps Autism: A New Theory | url = http://www.time.com/time/health/article/0,8599,1889436,00.html | date = 2009-04-07 | magazine = Time | url-status = dead | archive-url = https://web.archive.org/web/20130328002532/http://www.time.com/time/health/article/0,8599,1889436,00.html | archive-date =2013-03-28 }}

Oxidative stress, oxidative DNA damage and disruptions of DNA repair have been postulated to play a role in the etiopathology of both ASD and schizophrenia.{{cite journal | vauthors = Markkanen E, Meyer U, Dianov GL | title = DNA Damage and Repair in Schizophrenia and Autism: Implications for Cancer Comorbidity and Beyond | journal = International Journal of Molecular Sciences | volume = 17 | issue = 6 | page = 856 | date = June 2016 | pmid = 27258260 | pmc = 4926390 | doi = 10.3390/ijms17060856 | doi-access = free }} Physiological factors and mechanisms influence by oxidative stress are believed to be highly influential to autism risk. Interactions between environmental and genetic factors may increase oxidative stress in children with autism.{{cite journal | vauthors = Bjørklund G, Meguid NA, El-Bana MA, Tinkov AA, Saad K, Dadar M, Hemimi M, Skalny AV, Hosnedlová B, Kizek R, Osredkar J, Urbina MA, Fabjan T, El-Houfey AA, Kałużna-Czaplińska J, Gątarek P, Chirumbolo S | display-authors = 6 | title = Oxidative Stress in Autism Spectrum Disorder | journal = Molecular Neurobiology | volume = 57 | issue = 5 | pages = 2314–2332 | date = May 2020 | pmid = 32026227 | doi = 10.1007/s12035-019-01742-2 | s2cid = 255484540 }} This theory hypothesizes that toxicity and oxidative stress may cause autism in some cases. Evidence includes genetic effects on metabolic pathways, reduced antioxidant capacity, enzyme changes, and enhanced biomarkers for oxidative stress. One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved.{{cite journal | vauthors = Kern JK, Jones AM | title = Evidence of toxicity, oxidative stress, and neuronal insult in autism | journal = Journal of Toxicology and Environmental Health Part B: Critical Reviews | volume = 9 | issue = 6 | pages = 485–499 | year = 2006 | pmid = 17090484 | doi = 10.1080/10937400600882079 | bibcode = 2006JTEHB...9..485K | type = Review | s2cid = 1096750 }} Polymorphism of genes involved metabolization of glutathione is evidenced by lower levels of total glutathione, and higher levels of oxidized glutathione in autistic children.{{cite journal | vauthors = Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A | title = Glutathione-related factors and oxidative stress in autism, a review | journal = Current Medicinal Chemistry | volume = 19 | issue = 23 | pages = 4000–4005 | year = 2012 | pmid = 22708999 | doi = 10.2174/092986712802002572 | type = Review }} Based on this theory, antioxidants may be a useful treatment for autism.{{cite journal | vauthors = Villagonzalo KA, Dodd S, Dean O, Gray K, Tonge B, Berk M | title = Oxidative pathways as a drug target for the treatment of autism | journal = Expert Opinion on Therapeutic Targets | volume = 14 | issue = 12 | pages = 1301–1310 | date = December 2010 | pmid = 20954799 | doi = 10.1517/14728222.2010.528394 | type = Review | s2cid = 44864562 }} Environmental factors can influence oxidative stress pre, peri, and postnatally and include heavy metals, infection, certain drugs, and toxic exposure from various sources including cigarette smoke, air pollutants, and organophosphate pesticides.

Beyond the genetic, epigenetic, and biological factors that can contribute to an autism diagnosis are theories related to the "autistic identity".{{Cite journal | vauthors = Moore I, Morgan G, Welham A, Russell G |date=November 2022 |title=The intersection of autism and gender in the negotiation of identity: A systematic review and metasynthesis |journal=Feminism & Psychology |volume=32 |issue=4 |pages=421–442 |doi=10.1177/09593535221074806 |s2cid=246893906 |issn=0959-3535|doi-access=free }} It has been theorized that perceptions towards the characteristics of autistic individuals have been heavily influenced by neurotypical ideologies and social norms.

The social construct theory says that the boundary between normal and abnormal is subjective and arbitrary, so autism does not exist as an objective entity, but only as a social construct. It further argues that autistic individuals themselves have a way of being that is partly socially constructed.{{cite book|isbn=0-674-00412-4| vauthors = Hacking I | title = The Social Construction of What? |publisher=Harvard University Press|year=1999|pages=114–123}}

Mild and moderate variations of autism are particular targets of the theory that social factors determine what it means to be autistic. The theory hypothesizes that individuals with these diagnoses inhabit the identities that have been ascribed to them, and promote their sense of well-being by resisting or appropriating autistic ascriptions.{{cite book |chapter= The dialectics of autism: theorizing autism, performing autism, remediating autism, and resisting autism |title= Constructing Autism: Unravelling the 'Truth' and Understanding the Social | vauthors = Nadesan MH |publisher=Routledge |isbn=0-415-32181-6 |year=2005 |pages=179–213}}

Lynn Waterhouse suggests that autism has been reified, in that social processes have endowed it with more reality than is justified by the scientific evidence.{{cite book| vauthors = Waterhouse L |title=Rethinking Autism: Variation and Complexity|url=https://books.google.com/books?id=IaFY8r0rpn8C&pg=PA24|year=2013|publisher=Academic Press|isbn=978-0-12-415961-7|page=24|quote=Although autism spectrum disorder has not been proven to exist either as a set of meaningful subgroups, or as the expression of a unifying deficit or causal pattern, nonetheless, autism appears to have been unified as a real entity in public opinion... Some researchers have argued that, over time, autism has been transformed from a hypothesis to an assumed reality. This transformation is called reification. Reification is the conversion of a theorized entity into something assumed and believed to be real... the intense public discussion of autism, the long history of autism in the diagnostic manuals of the American Psychiatric Association, and the long history of autism research are in full view, and they all have made autism seem more concrete and less hypothetical.}}

Although social construction of the autistic identity can have a positive impact on the well-being and treatment of autistic individuals, that is not always the case when the individuals in question belong to historically marginalized populations.

Many studies have presented evidence for and against association of autism with viral infection after birth. Laboratory rats infected with Borna disease virus show some symptoms similar to those of autism but blood studies of autistic children show no evidence of infection by this virus. Members of the herpes virus family may have a role in autism, but the evidence so far is anecdotal. Viruses have long been suspected as triggers for immune-mediated diseases such as multiple sclerosis but showing a direct role for viral causation is difficult in those diseases, and mechanisms, whereby viral infections could lead to autism, are speculative.

{{See also|Evolutionary psychology}}

Research exploring the evolutionary benefits of autism and associated genes suggests that people with autistic traits may have facilitated crucial advancements in technology and knowledge of natural systems in the course of human development.{{cite web | vauthors = Spikins P |date=March 27, 2017 |title=How our autistic ancestors played an important role in human evolution |url=https://theconversation.com/how-our-autistic-ancestors-played-an-important-role-in-human-evolution-73477 |website=The Conversation }}{{cite book | vauthors = Spikins P |title=Recent Advances in Autism Spectrum Disorders - Volume II |date=March 6, 2013 | veditors = Fitzgerald M |chapter=The Stone Age Origins of Autism}} It has been suggested that these trait advantages may have resulted from the exchange of socially beneficial traits with ones that promote technological skills and systematic thought processes. In future studies, autism may prove similar to diseases such as sickle cell anemia, that demonstrate balanced polymorphism.{{cite journal | vauthors = Lomelin DE |date=2010 |title=An Examination of Autism Spectrum Disorders in Relation to Human Evolution and Life History Theory |url=https://digitalcommons.unl.edu/nebanthro/57/ |journal=Nebraska Anthropologist |volume=57}}

A 2011 study proposed the "Solitary Forager Hypothesis" in which autistic traits, including increased abilities for spatial intelligence, concentration and memory, could have been naturally selected to enable self-sufficient foraging in a more solitary environment.{{cite journal | vauthors = Reser JE | title = Conceptualizing the autism spectrum in terms of natural selection and behavioral ecology: the solitary forager hypothesis | journal = Evolutionary Psychology | volume = 9 | issue = 2 | pages = 207–238 | date = May 2011 | pmid = 22947969 | doi = 10.1177/147470491100900209 | s2cid = 25378900 | doi-access = free | pmc = 10480880 }}{{cite web |date=June 3, 2011 |title=Autism may have had advantages in humans' hunter-gatherer past, researcher believes |url=https://www.sciencedaily.com/releases/2011/06/110603122849.htm |website=ScienceDaily }}{{cite web | vauthors = Rudacille D |date=8 July 2011 |title=Lonely hunters |url=https://www.spectrumnews.org/opinion/lonely-hunters/ |website=Spectrum}} The author notes that such individuals likely foraged by themselves while occasionally interacting with intimate people or groups. A study conducted by Spikins et al. (2016) examined the role of Asperger syndrome as "an alternative pro-social adaptive strategy", which may have developed as a result of the emergence of "collaborative morality" in the context of small-scale hunter-gathering. The authors further suggest that "mutual interdependence of different social strategies" may have "contributed to the rise of innovation and large scale social networks".{{cite journal | vauthors = Spikins P, Wright B, Hodgson D |date=1 October 2016 |title=Are there alternative adaptive strategies to human pro-sociality? The role of collaborative morality in the emergence of personality variation and autistic traits |journal=Time and Mind |volume=9 |issue=4 |pages=289–313 |doi=10.1080/1751696X.2016.1244949 |issn=1751-696X |s2cid=151820168|doi-access=free }}

Conversely, noting the failure to find specific alleles that reliably cause autism or rare mutations that account for more than 5% of the heritable variation in autism established by twin and adoption studies, research in evolutionary psychiatry has concluded that it is unlikely that there is or has been selection pressure for autism when considering that, like schizophrenics, autistic people and their siblings tend to have fewer offspring on average than non-autistic people, and instead that autism is probably better explained as a by-product of adaptive traits caused by antagonistic pleiotropy and by genes that are retained due to a fitness landscape with an asymmetric distribution.{{cite book|last=Nesse|first=Randolph M.|author-link=Randolph M. Nesse|year=2019|chapter=14. Minds Unbalanced on Fitness Cliffs|title=Good Reasons for Bad Feelings: Insights from the Frontier of Evolutionary Psychiatry|place=New York|publisher=Dutton|pages=245–261|isbn=978-1101985663}}{{cite book|last=Nesse|first=Randolph M.|editor-last=Buss|editor-first=David M.|editor-link=David Buss|year=2016|orig-year=2005|chapter=43. Evolutionary Psychology and Mental Health|title=The Handbook of Evolutionary Psychology, Volume 2: Integrations|place=Hoboken, NJ|publisher=Wiley|edition=2nd|pages=1018–1019|isbn=978-1118755808}}{{cite magazine|last=Nesse|first=Randolph M.|date=March 4, 2019|title=The Puzzle of the Unbalanced Mind|magazine=Psychology Today|url=https://www.psychologytoday.com/us/articles/201903/the-puzzle-the-unbalanced-mind|access-date=October 13, 2024}}

{{Main|Archaic human admixture with modern humans}}

{{further|Neanderthal genetics}}

File:Homo sapiens sapiens, Oase, Rumänien (Daniela Hitzemann).jpg with around 7.3% Neanderthal DNA (from an ancestor 4–6 generations back){{cite journal |first1=Q. |last1=Fu |first2=M. |last2=Hajdinjak |first3=O. T. |last3= Moldovan |display-authors=3 |first4=S. |last4=Constantin |first5=S. |last5= Mallick |first6=Pontus |last6=Skoglund |first7=N. |last7=Patterson |first8=N. |last8=Rohland |first9=I. |last9=Lazaridis |first10=B. |last10=Nickel |first11=B. |last11=Viola |first12=Kay |last12=Prüfer |first13=M. |last13=Meyer |first14=J. |last14=Kelso |first15=D |last15=Reich |first16=S. |last16=Pääbo |author-link16=Svante Pääbo |title=An early modern human from Romania with a recent Neanderthal ancestor |journal=Nature |year=2015 |volume=524 |issue=7564 |pages=216–219 |doi=10.1038/nature14558 |pmid=26098372 |pmc=4537386 |bibcode=2015Natur.524..216F}}|alt=A dark-skinned man with black, shiny hair going down to his shoulders, a slight moustache, a goatee, brown eyes, weak eyebrows, wearing a tailored shirt and holding a long spear to support himself]]

One theory on the evolutionary and biological origins of autism traits in Homo sapiens that has gained recent attention in the 2010s and 2020s is that some genes linked to autism may have originated from early humans crossbreeding with Neanderthals, an extinct group of archaic humans (generally regarded as a distinct species, Homo neanderthalensis, though some regard it as a subspecies of Homo sapiens, referred to as H. sapiens neanderthalensis) who lived in Eurasia until about 40,000 years ago.

A possible link between autism spectrum disorders (ASDs) and Neanderthal DNA was identified in 2009, pending genome sequencing.{{cite web |last1=Rehnström |first1=Karola |title=Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate |url=https://www.julkari.fi/bitstream/handle/10024/79929/4c9e1288-3f5a-48be-985f-1162381bcf02.pdf?sequence=1&isAllowed=y |website=Julkari |publisher=National Institute for Health and Welfare (Finland) |access-date=24 March 2024}}

The first Neanderthal genome sequence was published in 2010, and strongly indicated interbreeding between Neanderthals and early modern humans.{{cite journal |last1=Green |first1=R. E. |last2=Krause |first2=J. |last3=Briggs |first3=A. W. |display-authors=3 |last4=Maricic |first4=T. |last5=Stenzel |first5=U. |last6=Kircher |first6=M. |last7=Patterson |first7=N. |last8=Li |first8=H. |last9=Zhai |first9=W. |last10=Fritz |first10=M. H. Y. |last11=Hansen |first11=N. F. |last12=Durand |first12=E. Y. |last13=Malaspinas |first13=A. S. |last14=Jensen |first14=J. D. |last15=Marques-Bonet |first15=T. |last16=Alkan |first16=C. |last17=Prüfer |first17=K. |last18=Meyer |first18=M. |last19=Burbano |first19=H. A. |last20=Good |first20=J. M. |last21=Schultz |first21=R. |last22=Aximu-Petri |first22=A. |last23=Butthof |first23=A. |last24=Hober |first24=B. |last25=Hoffner |first25=B. |last26=Siegemund |first26=M. |last27=Weihmann |first27=A. |last28=Nusbaum |first28=C. |last29=Lander |first29=E. 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D. |last7=Comas |first7=D. |last8=Lalueza-Fox |first8=C. |last9=Caramelli |first9=D.|title=North African populations carry the signature of admixture with Neandertals |journal=PLOS ONE |year= 2012 |volume=7 |issue=10 |pages=e47765 |doi=10.1371/journal.pone.0047765 |pmid=23082212 |pmc=3474783 |bibcode=2012PLoSO...747765S|doi-access=free }} The genomes of all studied modern populations contain Neanderthal DNA.{{cite journal |last1=Sankararaman |first1=S.|last2=Mallick |first2=S. |last3=Dannemann |first3=M. |last4=Prüfer |first4=K. |last5=Kelso |first5=J. |last6=Pääbo |first6=S. |author-link6=Svante Pääbo |last7=Patterson |first7=N. |last8=Reich |first8=D. |title=The genomic landscape of Neanderthal ancestry in present-day humans |journal=Nature |year= 2014 |volume=507 |issue=7492 |pages=354–357 |doi=10.1038/nature12961 |pmid=24476815 |pmc=4072735 |bibcode=2014Natur.507..354S}}{{cite journal |doi=10.1093/molbev/msr024 |title=An X-linked haplotype of Neandertal origin is present among all non-African populations |year=2011 |last1=Yotova |first1=V. |last2=Lefebvre |first2=J.-F. |last3=Moreau |first3=C. |display-authors=3 |last4=Gbeha |first4=E. |last5=Hovhannesyan |first5=K. |last6=Bourgeois |first6=S. |last7=Bédarida |first7=S. |last8=Azevedo |first8=L. |last9=Amorim |first9=A. |last10=Sarkisian |first10=T. |last11=Avogbe |first11=P. 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V. |last20=Lachmann |first20=M. |last21=Douka |first21=K. |last22=Higham |first22=T. F. G. |last23=Slatkin |first23=M. |last24=Hublin |first24=J.-J. |last25=Reich |first25=D. |last26=Kelso |first26=J. |last27=Viola |first27=T. B. |last28=Pääbo |first28=S. |author-link28=Svante Pääbo |title=Genome sequence of a 45,000-year-old modern human from western Siberia |journal=Nature |year= 2014 |volume=514 |issue=7523 |pages=445–449 |doi=10.1038/nature13810 |pmid=25341783 |pmc=4753769 |bibcode=2014Natur.514..445F}} Various estimates exist for the proportion, such as 1–4% or 3.4–7.9% in modern Eurasians,{{cite journal |arxiv=1307.8263 |title=Maximum likelihood evidence for Neandertal admixture in Eurasian populations from three genomes |first1=K. |last1=Lohse |first2=L. A. F. |last2=Frantz |journal=Populations and Evolution |bibcode=2013arXiv1307.8263L |volume=1307 |year=2013 |page=8263}} or 1.8–2.4% in modern Europeans and 2.3–2.6% in modern East Asians.{{cite journal |last1=Prüfer |first1=K. |last2=de Filippo |first2=C. |last3=Grote | first3=S. |last4=Mafessoni |first4=F. |last5=Korlević |first5=P. |last6=Hajdinjak |first6=M. |title=A high-coverage Neandertal genome from Vindija Cave in Croatia |journal=Science |year=2017 |doi=10.1126/science.aao1887 |pmid=28982794 |pmc=6185897 |display-authors=etal |volume=358 |issue=6363 |pages=655–658 |bibcode=2017Sci...358..655P}} Pre-agricultural Europeans appear to have had similar, or slightly higher, percentages to modern East Asians, and the numbers may have decreased in the former due to dilution with a group of people which had split off before Neanderthal introgression.{{sfn|Reich|2018}}

Typically, studies have reported finding no significant levels of Neanderthal DNA in Sub-Saharan Africans, but a 2020 study detected 0.3-0.5% in the genomes of five African sample populations, likely the result of Eurasians back-migrating and interbreeding with Africans, as well as human-to-Neanderthal gene flow from dispersals of Homo sapiens preceding the larger Out-of-Africa migration, and also showed more equal Neanderthal DNA percentages for European and Asian populations.{{cite journal |first1=L. |last1=Chen |first2=A. B. |last2=Wolf |first3=W. |last3=Fu |first4=J. M. |last4=Akey |year=2020 |title=Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals |journal=Cell |volume=180 |issue=4 |pages=677–687.e16 |doi=10.1016/j.cell.2020.01.012 |pmid=32004458 |s2cid=210955842|doi-access=free }} Such low percentages of Neanderthal DNA in all present day populations indicate infrequent past interbreeding,{{cite journal |first=S. |last=Pääbo |author-link=Svante Pääbo |title=The diverse origins of the human gene pool |journal=Nature Reviews Genetics |volume=16 |number=6 |pages=313–314 |year=2015 | doi=10.1038/nrg3954 |pmid=25982166 |s2cid=5628263}} unless interbreeding was more common with a different population of modern humans which did not contribute to the present day gene pool.{{sfn|Reich|2018}} Of the inherited Neanderthal genome, 25% in modern Europeans and 32% in modern East Asians may be related to viral immunity.{{cite journal |first1=D. |last1=Enard |first2=D. A. |last2=Petrov |year=2018 |title=Evidence that RNA viruses drove of adaptive introgression between Neanderthals and modern humans |journal=Cell |volume=175 |issue=2 |pages=360–371 |doi=10.1016/j.cell.2018.08.034 |pmc=6176737 |pmid=30290142}} In all, approximately 20% of the Neanderthal genome appears to have survived in the modern human gene pool.{{cite journal |title=Resurrecting surviving Neandertal lineages from modern human genomes |journal=Science |volume=343 |issue=6174 |pages=1017–1021 |year=2014 |bibcode=2014Sci...343.1017V |last1=Vernot |first1=B. |last2=Akey |first2=J. M. |doi=10.1126/science.1245938 |pmid=24476670 |s2cid=23003860|doi-access=free }}

Due to their small population and resulting reduced effectivity of natural selection, Neanderthals accumulated several weakly harmful mutations, which were introduced to and slowly selected out of the much larger modern human population; the initial hybridised population may have experienced up to a 94% reduction in fitness compared to contemporary humans. By this measure, Neanderthals may have substantially increased in fitness.{{cite journal |first1=I. |last1=Juric |first2=S. |last2=Aeschbacher |first3=G. |last3=Coop |year=2016 |title=The strength of selection against Neanderthal introgression |journal=PLOS Genetics |volume=12 |issue=11 |pages=e1006340 |doi=10.1371/journal.pgen.1006340 |pmid=27824859 |pmc=5100956 |doi-access=free }} A 2017 study focusing on archaic genes in Turkey found associations with coeliac disease, malaria severity and Costello syndrome.{{cite journal |first1=R. O. |last1=Taskent |first2=N. D. |last2=Alioglu |first3=E. |last3=Fer |display-authors=et al. |year=2017 |title=Variation and functional impact of Neanderthal ancestry in Western Asia |journal=Genome Biology and Evolution |volume=9 |issue=12 |pages=3516–3624 |doi=10.1093/gbe/evx216 |pmc=5751057 |pmid=29040546}}

Nonetheless, some genes may have helped modern East Asians adapt to the environment; the putatively Neanderthal Val92Met variant of the MC1R gene, which may be weakly associated with red hair and UV radiation sensitivity,{{cite journal |last1=Zorina-Lichtenwalter |first1=K. |last2=Lichtenwalter |first2=R. N. |last3=Zaykin |first3=D. V. |display-authors=et al. |title=A study in scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect |journal=Human Molecular Genetics |year= 2019 |volume=28 |issue=12 |pages=2093–2106 |doi=10.1093/hmg/ddz018 |pmid=30657907 |pmc=6548228 |doi-access=free}} is primarily found in East Asian, rather than European, individuals.{{cite journal |last1=Ding |first1=Q. |last2=Hu |first2=Y. |last3=Xu |first3=S. |last4=Wang |first4=C.-C. |last5=Li |first5=H. |last6=Zhang |first6=R. |last7=Yan |first7=S. |last8=Wang |first8=J. |last9=Jin |first9=L.|title=Neanderthal origin of the haplotypes carrying the functional variant Val92Met in the MC1R in modern humans |journal=Molecular Biology and Evolution |year= 2014 |volume=31 |issue=8 |pages=1994–2003 |doi=10.1093/molbev/msu180 |pmid=24916031 |doi-access=free}} "We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (~5%), moderate in continental East Asians (~30%), and high in Taiwanese aborigines (60–70%)." Some genes related to the immune system appear to have been affected by introgression, which may have aided migration,{{cite journal |first1=L. |last1=Ségurel |first2=L. |last2=Quintana-Murci |year=2014 |title=Preserving immune diversity through ancient inheritance and admixture |journal=Current Opinion in Immunology |volume=30 |pages=79–84 |doi=10.1016/j.coi.2014.08.002 |pmid=25190608}} such as OAS1,{{cite journal |first1=F. L. |last1=Mendez |first2=J. C. |last2=Watkins |first3=M. F. |last3=Hammer |year=2013 |title=Neandertal origin of genetic variation at the cluster of OAS immunity genes |journal=Molecular Biology and Evolution |volume=30 |issue=4 |pages=798–801 |doi=10.1093/molbev/mst004 |pmid=23315957 |s2cid=2839679 |url=http://pdfs.semanticscholar.org/4960/a4cb348c36a636721213898bce2c4fd99e4e.pdf |archive-url=https://web.archive.org/web/20190223155415/http://pdfs.semanticscholar.org/4960/a4cb348c36a636721213898bce2c4fd99e4e.pdf |url-status=dead |archive-date=2019-02-23}} STAT2,{{cite journal |first1=F. L. |last1=Mendez |first2=J. C. |last2=Watkins |first3=M. F. |last3=Hammer |title=A haplotype at STAT2 introgressed from Neanderthals and serves as a candidate of positive selection in Papua New Guinea |journal=American Journal of Human Genetics |volume=91 |issue=2 |year=2012 |pages=265–274 |doi=10.1016/j.ajhg.2012.06.015 |pmc=3415544 |pmid=22883142}} TLR6, TLR1, TLR10,{{cite journal |first1=M. |last1=Dannemann |first2=A. A. |last2=Andrés |first3=J. |last3=Kelso |year=2016 |title=Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human toll-like receptors |journal=American Journal of Human Genetics |volume=98 |issue=1 |pages=22–33 |doi=10.1016/j.ajhg.2015.11.015 |pmc=4716682 |pmid=26748514}} and several related to immune response.{{cite journal |first1=Y. |last1=Nédélec |first2=J. |last2=Sanz |first3=G. |last3=Baharian |display-authors=et al. |year=2016 |title=Genetic ancestry and natural selection drive population differences in immune responses to pathogens |journal=Cell |volume=167 |issue=3 |pages=657–669 |doi=10.1016/j.cell.2016.09.025 |pmid=27768889 |doi-access=free}}{{efn|OAS1 and STAT2 both are associated with fighting viral inflections (interferons), and the listed toll-like receptors (TLRs) allow cells to identify bacterial, fungal, or parasitic pathogens. African origin is also correlated with a stronger inflammatory response.}} In addition, Neanderthal genes have also been implicated in the structure and function of the brain,{{efn|Higher levels of Neanderthal-derived genes are associated with an occipital and parietal bone shape reminiscent to that of Neanderthals, as well as modifications to the visual cortex and the intraparietal sulcus (associated with visual processing).{{cite journal |first1=M. D. |last1=Gregory |first2=J. S. |last2=Kippenhan |first3=D. P. |last3=Eisenberg |display-authors=et al. |year=2017 |title=Neanderthal-derived genetic variation shapes modern human cranium and brain |journal=Scientific Reports |volume=7 |issue=1 |page=6308 |doi=10.1038/s41598-017-06587-0 |pmid=28740249 |pmc=5524936 |bibcode=2017NatSR...7.6308G}}}} keratin filaments, sugar metabolism, muscle contraction, body fat distribution, enamel thickness and oocyte meiosis.{{cite journal |first1=O. |last1=Dolgova |first2=O. |last2=Lao |year=2018 |title=Evolutionary and medical consequences of archaic introgression into modern human genomes |journal=Genes |volume=9 |issue=7 |page=358 |doi=10.3390/genes9070358 |pmc=6070777 |pmid=30022013 |doi-access=free}} Nonetheless, a large portion of surviving introgression appears to be non-coding ("junk") DNA with few biological functions.{{sfn|Reich|2018}}

A 2016 study indicated that human-Neanderthal gene variance may be involved in autism, with chromosome 16 section 16p11.2 deletions playing a large role.{{cite news |title=Human-Neanderthal Gene Variance is Involved in Autism |url=https://neurosciencenews.com/neuroscience-evolution-genetics-autism-4778/ |access-date=24 March 2024 |publisher=Neuroscience News |date=4 August 2016}}{{cite news |last1=McCarthy |first1=Michael |title=Human-Neanderthal gene variance is involved in autism |url=https://medicalxpress.com/news/2016-08-human-neanderthal-gene-variance-involved-inautism.html |access-date=24 March 2024 |publisher=Medical Express |date=4 August 2016}}

A 2017 study reported finding that the more Neanderthal DNA a person has in their genome, the more closely the brain of the individual would resemble that of a Neanderthal. The study also found that parts of the Neanderthal brain related to tool use and visual discrimination may have also experienced evolutionary or adaptational "trade-offs" with the "social brain", as also found in scientific studies on autism.{{cite journal |last1=Gregory |first1=Michael D. |last2=Kippenhan |first2=J. Shane |last3=Eisenberg |first3=Daniel P. |last4=Kohn |first4=Philip D. |last5=Dickinson |first5=Dwight |last6=Mattay |first6=Venkata S. |last7=Chen |first7=Qiang |last8=Weinberger |first8=Daniel R. |last9=Saad |first9=Ziad S. |last10=Berman |first10=Karen F. |title=Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain |journal=Scientific Reports |date=24 July 2017 |volume=7 |issue=1 |page=6308 |doi=10.1038/s41598-017-06587-0 |pmid=28740249 |pmc=5524936 |bibcode=2017NatSR...7.6308G }} A 2023 study also found evidence that Neanderthal single nucleotide polymorphisms (SNPs) likely play a "significant role" in autism susceptibility and heritability in autism populations across the United States. According to the study, "Although most studies on autism genomics focus on the deleterious nature of variants, there is the possibility some of these autism-associated Neanderthal SNPs have been under weak positive selection. In support, recent studies have identified genetic variants implicated in both autism and high intelligence. Meanwhile, autistic people often perform better on tests of fluid intelligence than neurotypicals."{{Citation needed|date=April 2024|reason=previously cited a preprint}}

Another 2017 study that analyzed 68 genes associated with neurodevelopmental disorders, including autism, found that these disorders were also affected by natural selection and interbreeding between Homo sapiens and other archaic human species. The study also recommended further research into the link between Neanderthal single nucleotide polymorphisms (SNPs) and neurodevelopmental disorders, including autism, in modern-day humans.{{cite journal |last1=Mozzi |first1=Alessandra |last2=Forni |first2=Diego |last3=Cagliani |first3=Rachele |last4=Pozzoli |first4=Uberto |last5=Clerici |first5=Mario |last6=Sironi |first6=Manuela |title=Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders |journal=Scientific Reports |date=21 July 2017 |volume=7 |issue=6116 |page=6116 |doi=10.1038/s41598-017-06440-4 |pmid=28733602 |pmc=5522412 |bibcode=2017NatSR...7.6116M |hdl=2434/554557 |hdl-access=free }}

A 2021 study confirmed these findings, noting that "the protective allele of rs7170637(A) CYFIP1, [one of the genes associated with autism spectrum disorder (ASD)], was present in primates to Neanderthals, and reemerged in modern humans, while absent in early modern humans"; "identified significant positive selection signals in 18 ASD risk SNPs"; that "ancient genome analysis identified de novo mutations...representing genes involved in cognitive function...and conserved evolutionary selection clusters"; and that "relative enrichment of the ASD risk SNPs from the respective evolutionary cluster or biological interaction networks may help in addressing the phenotypic diversity in ASD", with "cognitive genomic tradeoff signatures impacting the biological networks [explaining] the paradoxical phenotypes in ASD".{{cite journal |last1=Prakash |first1=Anil |last2=Banerjee |first2=Moinak |title=Genomic selection signatures in autism spectrum disorder identifies cognitive genomic tradeoff and its relevance in paradoxical phenotypes of deficits versus potentialities |journal=Scientific Reports |date=13 May 2021 |volume=11 |issue=10245 |page=10245 |doi=10.1038/s41598-021-89798-w |pmid=33986442 |pmc=8119484 |bibcode=2021NatSR..1110245P }}

{{Main|Refrigerator mother}}

Psychologist Bruno Bettelheim believed that autism was linked to early childhood trauma, and his work was highly influential for decades both in the medical and popular spheres. In his discredited theory, he blamed the mothers of individuals with autism for having caused their child's condition through the withholding of affection.{{cite book | vauthors = Bettelheim B |title= The Empty Fortress: Infantile Autism and the Birth of the Self |year= 1967 |publisher= Free Press |isbn= 0-02-903140-0 |authorlink= Bruno Bettelheim |url-access= registration |url= https://archive.org/details/emptyfortressinf00bett_0 }} Leo Kanner, who first described autism,{{cite journal | vauthors = Kanner L |title= Autistic disturbances of affective contact |journal= Nerv Child |volume=2 |pages=217–250 |year=1943 |authorlink= Leo Kanner}} Reprinted in {{cite journal | vauthors = Kanner L | title = Autistic disturbances of affective contact | journal = Acta Paedopsychiatrica | volume = 35 | issue = 4 | pages = 100–136 | year = 1968 | pmid = 4880460 }} suggested that parental coldness might contribute to autism.{{cite journal | vauthors = Kanner L | title = Problems of nosology and psychodynamics of early infantile autism | journal = The American Journal of Orthopsychiatry | volume = 19 | issue = 3 | pages = 416–426 | date = July 1949 | pmid = 18146742 | doi = 10.1111/j.1939-0025.1949.tb05441.x }} Although Kanner eventually renounced the theory, Bettelheim put an almost exclusive emphasis on it in both his medical and his popular books. Treatments based on these theories failed to help children with autism, and after Bettelheim's death, his reported rates of cure (around 85%) were found to be fraudulent.{{cite journal |journal= Skeptical Inquirer |volume=24 |issue=6 |pages=12–14 |year=2000 |title= The brutality of Dr. Bettelheim | vauthors = Gardner M |authorlink= Martin Gardner}}

The most recent scientific research has determined that changes to brain structures correlated with the development of autism can already be detected while the child is still in the womb, well before any vaccines are administered.{{cite web|url=https://scitechdaily.com/peering-into-the-womb-fetal-brain-scans-reveal-autism-clues/ |title=Peering Into the Womb: Fetal Brain Scans Reveal Autism Clues|author=King's College London|work=SciTechDaily|date=April 24, 2023}} Furthermore, scientific studies have consistently refuted a causal relationship between vaccinations and autism.{{cite journal | vauthors = Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D | title = Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations | journal = Pediatrics | volume = 118 | issue = 1 | pages = e139–e150 | date = July 2006 | pmid = 16818529 | doi = 10.1542/peds.2005-2993 | s2cid = 17981294 }}{{closed access}}{{cite journal | vauthors = Gross L | title = A broken trust: lessons from the vaccine--autism wars | journal = PLOS Biology | volume = 7 | issue = 5 | pages = e1000114 | date = May 2009 | pmid = 19478850 | pmc = 2682483 | doi = 10.1371/journal.pbio.1000114 | doi-access = free }}{{open access}}{{cite journal | vauthors = Taylor LE, Swerdfeger AL, Eslick GD | title = Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies | journal = Vaccine | volume = 32 | issue = 29 | pages = 3623–3629 | date = June 2014 | pmid = 24814559 | doi = 10.1016/j.vaccine.2014.04.085 }}{{open access}}

Despite this, some parents believe that vaccinations cause autism; they therefore delay or avoid immunizing their children (for example, under the "vaccine overload" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism,{{cite journal | vauthors = Hilton S, Petticrew M, Hunt K | title = 'Combined vaccines are like a sudden onslaught to the body's immune system': parental concerns about vaccine 'overload' and 'immune-vulnerability' | journal = Vaccine | volume = 24 | issue = 20 | pages = 4321–4327 | date = May 2006 | pmid = 16581162 | doi = 10.1016/j.vaccine.2006.03.003 }}{{open access}} even though this hypothesis has no scientific evidence and is biologically implausible{{cite journal | vauthors = Gerber JS, Offit PA | title = Vaccines and autism: a tale of shifting hypotheses | journal = Clinical Infectious Diseases | volume = 48 | issue = 4 | pages = 456–461 | date = February 2009 | pmid = 19128068 | pmc = 2908388 | doi = 10.1086/596476 | type = Review | doi-access = free }} For a lay summary,). Diseases such as measles can cause severe disabilities and even death, so the risk of death or disability for an unvaccinated child is higher than the risk for a child who has been vaccinated.{{cite journal | vauthors = Paul R | title = Parents ask: Am I risking autism if I vaccinate my children? | journal = Journal of Autism and Developmental Disorders | volume = 39 | issue = 6 | pages = 962–963 | date = June 2009 | pmid = 19363650 | doi = 10.1007/s10803-009-0739-y | s2cid = 34467853 }}{{closed access}} Despite medical evidence, antivaccine activism continues. A developing tactic is the "promotion of irrelevant research to justify the science underlying a questionable claim."{{cite journal | vauthors = Foster CA, Ortiz SM |title=Vaccines, Autism, and the Promotion of Irrelevant Research: A Science-Pseudoscience Analysis |journal=Skeptical Inquirer |date=2017 |volume=41 |issue=3 |pages=44–48 |url=https://www.csicop.org/si/show/vaccines_autism_and_the_promotion_of_irrelevant_research_a_science-pseudosc |archive-url=https://web.archive.org/web/20181006204019/https://www.csicop.org/si/show/vaccines_autism_and_the_promotion_of_irrelevant_research_a_science-pseudosc |url-status=dead |archive-date=2018-10-06 |access-date=6 October 2018}}

{{Main|MMR vaccine and autism}}

The MMR vaccine as a cause of autism is one of the most extensively debated hypotheses regarding the origins of autism. Andrew Wakefield et al. reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR.{{cite journal |vauthors=((The Editors Of The Lancet)) |date=February 2010 |title=Retraction--Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=375 |issue=9713 |pages=445 |doi=10.1016/S0140-6736(10)60175-4 |pmid=20137807 |s2cid=26364726}} For a lay summary, see {{cite news |date=2010-02-02 |title=Lancet accepts MMR study 'false' |work=BBC News |url=http://news.bbc.co.uk/2/low/health/8493753.stm |vauthors=Triggle N}} Although the paper, which was later retracted by the journal, concluded that there was no association between the MMR vaccine and autism, Wakefield nevertheless suggested a false notion during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose.{{cite journal |display-authors=6 |vauthors=Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA |date=February 1998 |title=Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children |journal=Lancet |volume=351 |issue=9103 |pages=637–641 |doi=10.1016/S0140-6736(97)11096-0 |pmid=9500320 |s2cid=439791}}{{Retracted paper|doi=10.1016/S0140-6736(10)60175-7|intentional=yes}} Administering the vaccines in three separate doses does not reduce the chance of adverse effects, and it increases the opportunity for infection by the two diseases not immunized against first.{{cite journal | vauthors = Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V | title = Vaccines for measles, mumps, rubella, and varicella in children | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 11 | pages = CD004407 | date = November 2021 | pmid = 34806766 | pmc = 8607336 | doi = 10.1002/14651858.CD004407.pub5 | collaboration = Cochrane Acute Respiratory Infections Group }}

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors.{{cite journal |display-authors=6 |vauthors=Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Valentine A, Davies SE, Walker-Smith JA |date=March 2004 |title=Retraction of an interpretation |journal=Lancet |volume=363 |issue=9411 |pages=750 |doi=10.1016/S0140-6736(04)15715-2 |pmid=15016483 |s2cid=5128036}} The retraction followed an investigation by The Sunday Times, which stated that Wakefield "acted dishonestly and irresponsibly".{{cite web |date=2008-11-02 |title=The MMR-autism crisis – our story so far |url=http://briandeer.com/mmr/lancet-summary.htm |access-date=2008-12-06 |vauthors=Deer B}} The Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, and the U.K. National Health Service have all concluded that there is no evidence of a link between the MMR vaccine and autism.{{cite web |date=2008-12-23 |title=Measles, mumps, and rubella (MMR) vaccine |url=https://www.cdc.gov/vaccinesafety/concerns/mmr_vaccine.htm |access-date=2009-02-14 |publisher=Centers for Disease Control and Prevention}}{{cite web |year=2004 |title=Immunization safety review: vaccines and autism |url=http://www.iom.edu/CMS/3793/4705/20155.aspx |url-status=dead |archive-url=https://web.archive.org/web/20070623134938/http://www.iom.edu/CMS/3793/4705/20155.aspx |archive-date=2007-06-23 |access-date=2007-06-13 |publisher=Institute of Medicine, National Academy of Sciences}}{{cite web |title=MMR the facts |url=http://www.mmrthefacts.nhs.uk/ |url-status=dead |archive-url=https://web.archive.org/web/20070615000359/http://www.mmrthefacts.nhs.uk/ |archive-date=2007-06-15 |access-date=2007-06-13 |publisher=National Health Service}}

In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed. In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.{{cite journal |vauthors=Godlee F, Smith J, Marcovitch H |date=January 2011 |title=Wakefield's article linking MMR vaccine and autism was fraudulent |journal=BMJ |volume=342 |pages=c7452 |doi=10.1136/bmj.c7452 |pmid=21209060 |s2cid=43640126}}{{cite journal |vauthors=Deer B |date=January 2011 |title=How the case against the MMR vaccine was fixed |journal=BMJ |volume=342 |pages=c5347 |doi=10.1136/bmj.c5347 |pmid=21209059 |s2cid=46683674}}{{cite news |date=2011-01-05 |title=Study linking vaccine to autism was fraud |publisher=NPR |agency=Associated Press |url=https://www.npr.org/2011/01/05/132692497/journal-study-linking-vaccine-to-autism-was-fraud |access-date=2011-01-06 |archive-url=https://web.archive.org/web/20110107085338/http://www.npr.org/2011/01/05/132692497/journal-study-linking-vaccine-to-autism-was-fraud |archive-date=2011-01-07}}{{cite news |date=2011-01-06 |title=Retracted autism study an 'elaborate fraud,' British journal finds |location=Atlanta |url=http://edition.cnn.com/2011/HEALTH/01/05/autism.vaccines/index.html |archive-url=https://web.archive.org/web/20110106075649/http://edition.cnn.com/2011/HEALTH/01/05/autism.vaccines/index.html |url-status=dead |archive-date=January 6, 2011 |access-date=2011-01-06}}

{{Main|Thiomersal and vaccines}}

Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound thiomersal, a preservative that has been phased out from most childhood vaccinations in developed countries including US and the EU.{{cite web |year=2012 |title=Vaccines, blood and biologics: thimerosal in vaccines |url=https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm096228.htm#thi |archive-url=https://web.archive.org/web/20090606182209/http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm096228.htm#thi |url-status=dead |archive-date=June 6, 2009 |access-date=October 24, 2013 |publisher=US Food and Drug Administration}} There is no scientific evidence for a causal connection between thiomersal and autism, but parental concern about a relationship between thiomersal and vaccines has led to decreasing rates of childhood immunizations and increasing likelihood of disease outbreaks. In 1999, due to concern about the dose of mercury infants were being exposed to, the U.S. Public Health Service recommended that thiomersal be removed from childhood vaccines, and by 2002 the flu vaccine was the only childhood vaccine containing more than trace amounts of thimerosal. Despite this, autism rates did not decrease after the removal of thimerosal, in the US or other countries that also removed thimerosal from their childhood vaccines.{{Cite web |date=7 January 2008 |title=Mercury in vaccines as a cause of autism and autism spectrum disorders (ASDs): A failed hypothesis |url=https://sciencebasedmedicine.org/mercury-in-vaccines-and-autism-a-failed-hypothesis/ |work=Science-Based Medicine |vauthors=Gorski D}}

A causal link between thimerosal and autism has been rejected by international scientific and medical professional bodies including the American Medical Association,{{cite web | author = American Medical Association | date = 2004-05-18 | url = http://www.ama-assn.org/ama1/pub/upload/mm/36/press_iom_mmr.doc | title = AMA Welcomes New IOM Report Rejecting Link Between Vaccines and Autism | access-date = 2007-07-23 | archive-date = 2012-10-06 | archive-url = https://web.archive.org/web/20121006192113/http://www.ama-assn.org/ama1/pub/upload/mm/36/press_iom_mmr.doc | url-status = dead }} the American Academy of Pediatrics,{{cite web | author = American Academy of Pediatrics | date = 2004-05-18 | url = http://www.cispimmunize.org/fam/autism/thimerosal.htm | title = What Parents Should Know About Thimerosal | access-date = 2007-07-23 | archive-url = https://web.archive.org/web/20070708045514/http://www.cispimmunize.org/fam/autism/thimerosal.htm | archive-date = 2007-07-08 | url-status = dead }} the American College of Medical Toxicology,{{cite journal | vauthors = Kurt TL | title = ACMT position statement: the Iom report on thimerosal and autism | journal = Journal of Medical Toxicology | volume = 2 | issue = 4 | pages = 170–171 | date = December 2006 | pmid = 18072140 | pmc = 3550071 | doi = 10.1007/BF03161188 | url = http://jmt.pennpress.org/strands/jmt/pdfHandler.pdf?issue=20060204&file=20060204_170_171.pdf | archive-url = https://wayback.archive-it.org/all/20080229034831/http://jmt.pennpress.org/strands/jmt/pdfHandler.pdf?issue=20060204&file=20060204_170_171.pdf | archive-date = 2008-02-29 }} the Canadian Paediatric Society,{{cite journal | author = Infectious Diseases and Immunization Committee, Canadian Paediatric Society | title = Autistic spectrum disorder: No causal relationship with vaccines | journal = Paediatrics & Child Health | volume = 12 | issue = 5 | pages = 393–398 | date = May 2007 | pmid = 19030398 | pmc = 2528717 | url = http://cps.ca/english/statements/ID/pidnote_jun07.htm | access-date = 2008-10-17 | url-status = dead | archive-url = https://web.archive.org/web/20081202050830/http://www.cps.ca/english/statements/ID/PIDnote_Jun07.htm | archive-date = 2008-12-02 }} Also published (2007) in {{cite journal | vauthors = | title = Autistic spectrum disorder: No causal relationship with vaccines | journal = The Canadian Journal of Infectious Diseases & Medical Microbiology | volume = 18 | issue = 3 | pages = 177–179 | date = May 2007 | pmid = 18923720 | pmc = 2533550 | doi = 10.1155/2007/267957 | doi-access = free }}. the U.S. National Academy of Sciences, the Food and Drug Administration,{{cite web |date=2007-09-06 |url=https://www.fda.gov/cber/vaccine/thimerosal.htm |archive-url=https://web.archive.org/web/20011030175538/http://www.fda.gov/cber/vaccine/thimerosal.htm |url-status=dead |archive-date=October 30, 2001 |access-date=2007-10-01 |title= Thimerosal in vaccines |publisher= Center for Biologics Evaluation and Research, U.S. Food and Drug Administration}} Centers for Disease Control and Prevention, the World Health Organization,{{cite web |author= World Health Organization |year=2006 |url=https://www.who.int/features/qa/85/en/ |title= Questions and answers about autism spectrum disorders (ASD) |access-date=2014-11-02}} the Public Health Agency of Canada,{{cite journal | author = National Advisory Committee on Immunization | title = Thimerosal: updated statement. An Advisory Committee Statement (ACS) | journal = Canada Communicable Disease Report | volume = 33 | issue = ACS-6 | pages = 1–13 | date = July 2007 | pmid = 17663033 | url = http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/07vol33/acs-06/index_e.html }} and the European Medicines Agency.{{cite web | author = European Medicines Agency | date = 2004-03-24 | url = http://www.emea.europa.eu/pdfs/human/press/pus/119404en.pdf | title = EMEA Public Statement on Thiomersal in Vaccines for Human Use | access-date = 2007-07-22 | archive-url = https://web.archive.org/web/20070610154109/http://www.emea.europa.eu/pdfs/human/press/pus/119404en.pdf | archive-date = 2007-06-10 }}

• List of topics characterized as pseudoscience
• Sex differences in autism

{{reflist|group=lower-alpha}}

{{Reflist|30em}}

• {{cite book |first=D. |last=Reich |author-link=David Reich (geneticist) |year=2018 |chapter=Encounters with Neanderthals |title=Who we are and how we got here: ancient DNA and the new science of the human past |publisher=Oxford University Press |isbn=978-0-19-882125-0 |url={{google books |plainurl=yes |id=uLNSDwAAQBAJ |page=25}}}}

{{Pervasive developmental disorders}}

{{Autism resources}}

{{Portal bar|Psychiatry}}

Category:Social constructionism