Heritability of autism

Twin studies provide a unique opportunity to explore the genetic and environmental influences on autism spectrum disorder (ASD). By studying identical twins, who share identical DNA, and fraternal twins, who share about half of their DNA, researchers can estimate the heritability of autism by comparing the rates of when one twin is diagnosed with autism while the other is not in identical vs. fraternal twins. Twin studies are a helpful tool in determining the heritability of disorders and human traits in general. They involve determining concordance of characteristics between identical (monozygotic or MZ) twins and between fraternal (dizygotic or DZ) twins. Possible problems of twin studies are: (1) errors in diagnosis of monozygocity, and (2) the assumption that social environment sharing by DZ twins is equivalent to that of MZ twins.

A condition that is environmentally caused without genetic involvement would yield a concordance for MZ twins equal to the concordance found for DZ twins. In contrast, a condition that is completely genetic in origin would theoretically yield a concordance of 100% for MZ pairs and usually much less for DZ pairs depending on factors such as the number of genes involved and assortative mating.

An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome (IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.{{cite journal | vauthors = Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ | title = Genetic influences in irritable bowel syndrome: a twin study | journal = The American Journal of Gastroenterology | volume = 100 | issue = 6 | pages = 1340–4 | date = June 2005 | doi = 10.1111/j.1572-0241.2005.41700.x | pmid = 15929767 | s2cid = 24085444 }} An

example of a human characteristic that is extremely heritable is eye color, with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.{{cite journal | vauthors = Bito LZ, Matheny A, Cruickshanks KJ, Nondahl DM, Carino OB | title = Eye color changes past early childhood. The Louisville Twin Study | journal = Archives of Ophthalmology | volume = 115 | issue = 5 | pages = 659–63 | date = May 1997 | pmid = 9152135 | doi = 10.1001/archopht.1997.01100150661017 }}

Identical twin studies put autism's heritability in a range between 36% and 95.7%, with concordance for a broader phenotype usually found at the higher end of the range.Twin studies (concordance in brackets):

• (0.8–1) {{cite web | vauthors = Ciaranello RD | url = http://www.narsad.org/news/newsletter/specialreports/archautism.html | title = The Neurobiology of Infantile Autism | work = NARSAD News Letter | publisher = National Alliance for Research on Schizophrenia and Depression | archive-url = https://web.archive.org/web/20051025162843/http://www.narsad.org/news/newsletter/specialreports/archautism.html | archive-date=2005-10-25 }}
• (0.8) {{cite web | vauthors = Kallen RJ | date = 3 May 2000 | url = http://www.autism-biomed.org/bricktwn.htm | title = CDC Reports a higher than expected prevalence of autism in Brick Township | archive-url = https://web.archive.org/web/20060620214216/http://www.autism-biomed.org/bricktwn.htm |archive-date=2006-06-20 | work = Autism Biomedical Information Network }}
• (0.91–0.93) {{cite web | vauthors = Dawson G | date = 16 September 1999 | url = http://faculty.washington.edu/dawson/Advocacy/Congress.html | title = Written testimony Public Health Subcommittee, United States Senate | archive-url = https://web.archive.org/web/20060219133921/http://faculty.washington.edu/dawson/Advocacy/Congress.html | archive-date=2006-02-19 }}
• (0.9) {{cite web | vauthors = Lang LH | url = http://www.parentsofallergicchildren.org/autism2.htm | title = Study points to chromosome site of autism gene | archive-url = https://web.archive.org/web/20010305022902/http://www.parentsofallergicchildren.org/autism2.htm | archive-date=2001-03-05 | work = UNC-CH School of Medicine }}
• (0.6–0.92) {{cite journal | vauthors = Muhle R, Trentacoste SV, Rapin I | title = The genetics of autism | journal = Pediatrics | volume = 113 | issue = 5 | pages = e472-86 | date = May 2004 | pmid = 15121991 | doi = 10.1542/peds.113.5.e472 | doi-access = free }}
• (0.6–0.8) {{cite journal | vauthors = Kurita H | title = [Current status of autism studies] | language = Japanese | journal = Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica | volume = 103 | issue = 1 | pages = 64–75 | year = 2001 | pmid = 11383012 | doi = }} Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population.

Notable twin studies have attempted to shed light on the heritability of autism.

A small-scale study in 1977 was the first of its kind to look into the heritability of autism. It involved 10 DZ twins and 11 MZ twins in which at least one twin in each pair showed infantile autism. It found a concordance of 36% in MZ twins compared to 0% for DZ twins. Concordance of "cognitive abnormalities" was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs discordant for autism, a biological hazard was believed to be associated with the condition.{{cite journal | vauthors = Folstein S, Rutter M | title = Infantile autism: a genetic study of 21 twin pairs | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines |issn =0021-9630 | eissn = 1469-7610 | oclc = 01307942 |volume = 18 | issue = 4 | pages = 297–321 | date = September 1977 | pmid = 562353 | doi = 10.1111/j.1469-7610.1977.tb00443.x }}

A 1979 case report discussed a pair of identical twins concordant for autism. The twins developed similarly until the age of 4, when one of them spontaneously improved. The other twin, who had had infrequent seizures, remained autistic. The report noted that genetic factors were not "all-important" in the development of twins.{{cite journal | vauthors = Wessels WH, Pompe van Meerdervoort M | title = Monozygotic twins with early infantile autism. A case report | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 55 | issue = 23 | pages = 955–7 | date = June 1979 | pmid = 572995 | doi = }}

In 1985, a study of twins enrolled with the UCLA Registry for Genetic Studies found a concordance of 95.7% for autism in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.{{cite journal | vauthors = Ritvo ER, Freeman BJ, Mason-Brothers A, Mo A, Ritvo AM | title = Concordance for the syndrome of autism in 40 pairs of afflicted twins | journal = The American Journal of Psychiatry | volume = 142 | issue = 1 | pages = 74–7 | date = January 1985 | pmid = 4038442 | doi = 10.1176/ajp.142.1.74 }}

In a 1989 study, Nordic countries were screened for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins were examined. Concordance of autism was found to be 91% in MZ and 0% in DZ pairs. The concordances for "cognitive disorder" were 91% and 30% respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress.{{cite journal | vauthors = Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M | title = A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | issn =0021-9630 | eissn = 1469-7610 | oclc = 01307942 |volume = 30 | issue = 3 | pages = 405–16 | date = May 1989 | pmid = 2745591 | doi = 10.1111/j.1469-7610.1989.tb00254.x }}

A British twin sample was reexamined in 1995 and a 60% concordance was found for autism in MZ twins vs. 0% concordance for DZ. It also found 92% concordance for a broader spectrum in MZ vs. 10% for DZ. The study concluded that "obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors."{{cite journal | vauthors = Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M | title = Autism as a strongly genetic disorder: evidence from a British twin study | journal = Psychological Medicine | volume = 25 | issue = 1 | pages = 63–77 | date = January 1995 | pmid = 7792363 | doi = 10.1017/S0033291700028099 | s2cid = 28907073 }}

A 1999 study looked at social cognitive skills in the general-population of children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.{{cite journal | vauthors = Scourfield J, Martin N, Lewis G, McGuffin P | title = Heritability of social cognitive skills in children and adolescents | journal = The British Journal of Psychiatry | volume = 175 | issue = 6 | pages = 559–64 | date = December 1999 | pmid = 10789354 | doi = 10.1192/bjp.175.6.559 | s2cid = 38743852 | url = http://jnnp.bmj.com/content/67/6/833.4.long }}

In 2000, a study looked at reciprocal social behavior in general-population identical twins. It found a concordance of 73% for MZ, i.e. "highly heritable", and 37% for DZ pairs.{{cite journal | vauthors = Constantino JN, Todd RD | title = Genetic structure of reciprocal social behavior | journal = The American Journal of Psychiatry | volume = 157 | issue = 12 | pages = 2043–5 | date = December 2000 | pmid = 11097975 | doi = 10.1176/appi.ajp.157.12.2043 }}

A 2004 study looked at 16 MZ twins and found a concordance of 43.75% for "strictly defined autism". Neuroanatomical differences (discordant cerebellar white and grey matter volumes) between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader phenotype.{{cite journal | vauthors = Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R, Reiss AL, Pearlson GD | display-authors = 6 | title = Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism | journal = The American Journal of Psychiatry | volume = 161 | issue = 3 | pages = 539–46 | date = March 2004 | pmid = 14992981 | doi = 10.1176/appi.ajp.161.3.539 }}

Another 2004 study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among monozygotic twins compared to siblings in a sample of 16 families. The study demonstrated significant aggregation of symptoms in twins. It also concluded that "the levels of clinical features seen in autism may be a result of mainly independent genetic traits."{{cite journal | vauthors = Kolevzon A, Smith CJ, Schmeidler J, Buxbaum JD, Silverman JM | title = Familial symptom domains in monozygotic siblings with autism | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 129B | issue = 1 | pages = 76–81 | date = August 2004 | pmid = 15274045 | doi = 10.1002/ajmg.b.30011 | s2cid = 31012683 }}

An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.{{cite journal | vauthors = Ronald A, Happé F, Bolton P, Butcher LM, Price TS, Wheelwright S, Baron-Cohen S, Plomin R | display-authors = 6 | title = Genetic heterogeneity between the three components of the autism spectrum: a twin study | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 45 | issue = 6 | pages = 691–699 | date = June 2006 | pmid = 16721319 | doi = 10.1097/01.chi.0000215325.13058.9d }}

One critic of the pre-2006 twin studies said that they were too small and their results can be plausibly explained on non-genetic grounds.{{cite book|chapter=Autism and genetics: much ado about very little|chapter-url=http://www.jayjoseph.net/MissingGeneChapters.html|access-date=2007-07-25| vauthors = Joseph J|title=The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes|date=2006|publisher=Algora|isbn=0-87586-410-4|archive-url=https://web.archive.org/web/20070927214327/http://www.jayjoseph.net/MissingGeneChapters.html|archive-date=2007-09-27|url-status=dead}}

In a 2015 meta-analysis of previously conducted twin studies, the authors found that genetics play a substantial role in the development of autism, contributing between 64% to 91% to the chances of developing autism.{{Cite journal |last=Tick |first=Beata |last2=Bolton |first2=Patrick |last3=Happé |first3=Francesca |last4=Rutter |first4=Michael |last5=Rijsdijk |first5=Frühling |date=May 2016 |title=Heritability of autism spectrum disorders: a meta‐analysis of twin studies |url=https://acamh.onlinelibrary.wiley.com/doi/10.1111/jcpp.12499 |journal=Journal of Child Psychology and Psychiatry |language=en |volume=57 |issue=5 |pages=585–595 |doi=10.1111/jcpp.12499 |issn=0021-9630 |pmc=4996332 |pmid=26709141}}

In a 2024 study of twins conducted by Martini et al., findings suggests that genetic factors have a greater influence on the stability of autistic traits compared to environmental factors.{{Cite journal |last=Martini |first=Miriam I. |last2=Butwicka |first2=Agnieszka |last3=Du Rietz |first3=Ebba |last4=Kanina |first4=Aleksandra |last5=Rosenqvist |first5=Mina A. |last6=Larsson |first6=Henrik |last7=Lichtenstein |first7=Paul |last8=Taylor |first8=Mark J. |date=September 2024 |title=Age effects on autism heritability and etiological stability of autistic traits |url=https://acamh.onlinelibrary.wiley.com/doi/10.1111/jcpp.13949 |journal=Journal of Child Psychology and Psychiatry |language=en |volume=65 |issue=9 |pages=1135–1144 |doi=10.1111/jcpp.13949 |issn=0021-9630|doi-access=free }}

A study of 99 autistic probands which found a 2.9% concordance for autism in siblings, and between 12.4% and 20.4% concordance for a "lesser variant" of autism.{{cite journal | vauthors = Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M, Bailey A, Rutter M | display-authors = 6 | title = A case-control family history study of autism | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines |issn =0021-9630 | eissn = 1469-7610 | oclc = 01307942| volume = 35 | issue = 5 | pages = 877–900 | date = July 1994 | pmid = 7962246 | doi = 10.1111/j.1469-7610.1994.tb02300.x }}

A study of 31 siblings of autistic children, 32 siblings of children with developmental delay, and 32 controls. It found that the siblings of autistic children, as a group, "showed superior spatial and verbal span, but a greater than expected number performed poorly on the set-shifting, planning, and verbal fluency tasks."{{cite journal | vauthors = Hughes C, Plumet MH, Leboyer M | title = Towards a cognitive phenotype for autism: increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | issn =0021-9630 | eissn = 1469-7610 | oclc = 01307942 | volume = 40 | issue = 5 | pages = 705–18 | date = July 1999 | pmid = 10433405 | doi = 10.1111/1469-7610.00487 }}

A 2005 Danish study looked at "data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity." It found an overall prevalence rate of roughly 0.08%. Prevalence of autism in siblings of autistic children was found to be 1.76%. Prevalence of autism among siblings of children with Asperger syndrome or PDD was found to be 1.04%. The risk was twice as high if the mother had been diagnosed with a psychiatric disorder. The study also found that "the risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age."{{cite journal | vauthors = Lauritsen MB, Pedersen CB, Mortensen PB | title = Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | issn =0021-9630 | eissn = 1469-7610 | oclc = 01307942 |volume = 46 | issue = 9 | pages = 963–71 | date = September 2005 | pmid = 16108999 | doi = 10.1111/j.1469-7610.2004.00391.x }}

A study in 2007 looked at a database containing pedigrees of 86 families with two or more autistic children and found that 42 of the third-born male children showed autistic symptoms, suggesting that parents had a 50% chance of passing on a mutation to their offspring. The mathematical models suggest that about 50% of autistic cases are caused by spontaneous mutations. The simplest model was to divide parents into two risk classes depending on whether the parent carries a pre-existing mutation that causes autism; it suggested that about a quarter of autistic children have inherited a copy number variation from their parents.{{cite journal | vauthors = Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, Law P, Qiu S, Lord C, Sebat J, Ye K, Wigler M | display-authors = 6 | title = A unified genetic theory for sporadic and inherited autism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 31 | pages = 12831–6 | date = July 2007 | pmid = 17652511 | pmc = 1933261 | doi = 10.1073/pnas.0705803104 | bibcode = 2007PNAS..10412831Z | doi-access = free }}

A 1994 study looked at the personalities of parents of autistic children, using parents of children with Down syndrome as controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive" compared to parents whose children did not have autism.{{cite journal | vauthors = Piven J, Wzorek M, Landa R, Lainhart J, Bolton P, Chase GA, Folstein S | title = Personality characteristics of the parents of autistic individuals | journal = Psychological Medicine | volume = 24 | issue = 3 | pages = 783–95 | date = August 1994 | pmid = 7991760 | doi = 10.1017/S0033291700027938 | s2cid = 20725041 }}

A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.{{cite journal | vauthors = Piven J, Palmer P, Jacobi D, Childress D, Arndt S | title = Broader autism phenotype: evidence from a family history study of multiple-incidence autism families | journal = The American Journal of Psychiatry | volume = 154 | issue = 2 | pages = 185–90 | date = February 1997 | pmid = 9016266 | doi = 10.1176/ajp.154.2.185 | doi-access = free }}

Autism was found to occur more often in families of physicists, engineers and scientists. 12.5% of the fathers and 21.2% of the grandfathers (both paternal and maternal) of children with autism were engineers, compared to 5% of the fathers and 2.5% of the grandfathers of children with other syndromes.{{cite journal| vauthors = Baron-Cohen S, Bolton P, Wheelwright S, Short L, Mead G, Smith A, Scahill V |year=1998 |title=Autism occurs more often in families of physicists, engineers, and mathematicians |url=http://www.autismresearchcentre.com/docs/papers/1998_BCetal_Maths.pdf |journal=Autism |volume=2 |issue= 3 |pages=296–301 |doi=10.1177/1362361398023008 |s2cid=146452233 |archive-url=https://web.archive.org/web/20060505122037/http://www.autismresearchcentre.com/docs/papers/1998_BCetal_Maths.pdf |archive-date=2006-05-05 |url-status=dead }} Other studies have yielded similar results.{{cite journal| vauthors = Baron-Cohen S, Wheelwright S, Stott C, Bolton P, Goodyer I |year=1997 |title=Is there a link between engineering and autism? |url=http://www.autismresearchcentre.com/docs/papers/1997_BCetal_Engineer.pdf |journal=Autism |volume=1 |issue=1 |pages=153–163 |archive-url=https://web.archive.org/web/20060505121710/http://www.autismresearchcentre.com/docs/papers/1997_BCetal_Engineer.pdf |archive-date=2006-05-05 |url-status=dead | doi = 10.1177/1362361397011010 |s2cid=145375886 }}{{cite journal | vauthors = Wheelwright S, Baron-Cohen S | title = The link between autism and skills such as engineering, maths, physics and computing: a reply to Jarrold and Routh | journal = Autism | volume = 5 | issue = 2 | pages = 223–7 | date = June 2001 | pmid = 11706868 | doi = 10.1177/1362361301005002010 | url = https://doi.org/10.1177/1362361301005002010 | access-date = October 5, 2020 | url-status = live | s2cid = 14554953 | archive-url = https://web.archive.org/web/20201005031105/https://journals.sagepub.com/doi/10.1177/1362361301005002010 | archive-date = October 5, 2020 }} Findings of this nature have led to the coinage of the term "geek syndrome".{{cite magazine | vauthors = Silberman S | url = https://www.wired.com/wired/archive/9.12/aspergers_pr.html | title = The Geek Syndrome. | archive-url = https://web.archive.org/web/20011218003739/http://www.wired.com/wired/archive/9.12/aspergers_pr.html | archive-date=2001-12-18 | magazine = Wired Magazine | date = December 2001 | access-date = December 10, 2006 }}

A 2001 study of brothers and parents of autistic boys looked into the phenotype in terms of one current cognitive theory of autism. The study raised the possibility that the broader autism phenotype may include a "cognitive style" (weak central coherence) that can confer information-processing advantages.{{cite journal | vauthors = Happé F, Briskman J, Frith U | title = Exploring the cognitive phenotype of autism: weak "central coherence" in parents and siblings of children with autism: I. Experimental tests | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | issn =0021-9630 | eissn = 1469-7610 | oclc = 01307942 |volume = 42 | issue = 3 | pages = 299–307 | date = March 2001 | pmid = 11321199 | doi = 10.1111/1469-7610.00723 }}

A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.{{cite journal | vauthors = Abramson RK, Ravan SA, Wright HH, Wieduwilt K, Wolpert CM, Donnelly SA, Pericak-Vance MA, Cuccaro ML | display-authors = 6 | title = The relationship between restrictive and repetitive behaviors in individuals with autism and obsessive compulsive symptoms in parents | journal = Child Psychiatry and Human Development | volume = 36 | issue = 2 | pages = 155–65 | year = 2005 | pmid = 16228144 | doi = 10.1007/s10578-005-2973-7 | s2cid = 44501937 }} Another 2005 study focused on sub-threshold autistic traits in the general population. It found that correlation for social impairment or competence between parents and their children and between spouses is about 0.4.{{cite journal | vauthors = Constantino JN, Todd RD | title = Intergenerational transmission of subthreshold autistic traits in the general population | journal = Biological Psychiatry | volume = 57 | issue = 6 | pages = 655–60 | date = March 2005 | pmid = 15780853 | doi = 10.1016/j.biopsych.2004.12.014 | s2cid = 7623717 }}

A 2005 report examined the family psychiatric history of 58 subjects with Asperger syndrome (AS) diagnosed according to DSM-IV criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia. Thirty five (60%) had a family history of depression. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.{{cite journal | vauthors = Ghaziuddin M | title = A family history study of Asperger syndrome | journal = Journal of Autism and Developmental Disorders | volume = 35 | issue = 2 | pages = 177–82 | date = April 2005 | pmid = 15909404 | doi = 10.1007/s10803-004-1996-4 | hdl = 2027.42/44625 | s2cid = 16544247 | hdl-access = free }}

According to a 2022 study held on 86 mother-child dyads across 18 months, "prior maternal depression didn’t predict child behavior problems later."{{cite web|url=https://neurosciencenews.com/depression-asd-moms-21298/|title=Half of Moms of Kids With Autism Have High Depressive Symptoms|date=August 26, 2022}}

{{Expand section|date=February 2014}}

It has been suggested that the twinning process itself is a risk factor

in the development of autism, presumably due to perinatal factors.{{cite journal | vauthors = Greenberg DA, Hodge SE, Sowinski J, Nicoll D | title = Excess of twins among affected sibling pairs with autism: implications for the etiology of autism | journal = American Journal of Human Genetics | volume = 69 | issue = 5 | pages = 1062–7 | date = November 2001 | pmid = 11590546 | pmc = 1274353 | doi = 10.1086/324191 }} However, three large-scale epidemiological studies have refuted this idea.{{cite journal | vauthors = Freitag CM | title = The genetics of autistic disorders and its clinical relevance: a review of the literature | journal = Molecular Psychiatry | volume = 12 | issue = 1 | pages = 2–22 | date = January 2007 | pmid = 17033636 | doi = 10.1038/sj.mp.4001896 | s2cid = 205678822 | doi-access = free }}{{cite journal | vauthors = Hallmayer J, Glasson EJ, Bower C, Petterson B, Croen L, Grether J, Risch N | title = On the twin risk in autism | journal = American Journal of Human Genetics | volume = 71 | issue = 4 | pages = 941–6 | date = October 2002 | pmid = 12297988 | pmc = 378547 | doi = 10.1086/342990 }} These studies took place in California, Sweden, and Australia. One study done in Western Australia, utilized the Maternal and Child Health Research Database that houses birth records for all infants born, including infants and later children diagnosed with autism spectrum disorder. During this study, the population analyzed for the incidence of Autism Spectrum Disorder was restricted to those children with birth years between 1980 and 1995. The focus was on the incidence of autism spectrum disorder in the twin population in comparison to the non twin population. The following two studies, explored the risk of Autism spectrum disorder in the twin population. The conclusion that the twinning process alone is not a risk factor was drawn. In these studies the data exemplified that both MZ twins will have autism spectrum disorder, but only one of the DZ twins will have autism spectrum disorder with an incidence rate of 90% in MZ twins compared to 0% in DZ twins. The high symmetry in MZ twins can explain the high symmetry of autism spectrum disorder in MZ twins outcome compared to DZ twins and non twin siblings.

{{See also|Missing heritability problem}}

Twin and family studies show that autism is a highly heritable condition, but they have left many questions for researchers, most notably:

• Why is fraternal twin concordance so low considering that identical twin concordance is high?
• Why are parents of autistic children typically non-autistic?
• Which factors could be involved in the failure to find a 100% concordance in identical twins?
• Is profound intellectual disability a characteristic of the genotype or something totally independent?

Clues to the first two questions come from studies that have shown that at least 30% of individuals with autism have spontaneous de novo mutations that occurred in the father's sperm or mother's egg that disrupt important genes for brain development. These spontaneous mutations are likely to cause autism in families where there is no family history of the disorder.{{cite journal | 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 | display-authors = 6 | title = The contribution of de novo coding mutations to autism spectrum disorder | journal = Nature | volume = 515 | issue = 7526 | pages = 216–21 | date = November 2014 | pmid = 25363768 | pmc = 4313871 | doi = 10.1038/nature13908 | bibcode = 2014Natur.515..216I }}

The concordance between identical twins is not quite 100% for two reasons, because these mutations have variable 'expressivity' and their effects manifest differently due to chance effects, epigenetic, and environmental factors. Also spontaneous mutations can potentially occur specifically in one embryo and not the other after conception.{{cite journal | vauthors = Gringras P, Chen W | title = Mechanisms for differences in monozygous twins | journal = Early Human Development | volume = 64 | issue = 2 | pages = 105–17 | date = September 2001 | pmid = 11440823 | doi = 10.1016/S0378-3782(01)00171-2 }} The likelihood of developing intellectual disability is dependent on the importance of the gene to brain development and how the mutation changes this function, also playing a role is the genetic and environmental background upon which a mutation occurs.{{cite journal | vauthors = Brandler WM, Sebat J | title = From de novo mutations to personalized therapeutic interventions in autism | journal = Annual Review of Medicine | volume = 66 | issue = 1 | pages = 487–507 | date = 14 January 2015 | pmid = 25587659 | doi = 10.1146/annurev-med-091113-024550 }}

The recurrence of the same mutations in multiple individuals affected by autism has led Brandler and Sebat to suggest that the spectrum of autism is breaking up into quanta of many different genetic disorders.

The most parsimonious explanation for cases of autism where a single child is affected and there is no family history or affected siblings is that a single spontaneous mutation that impacts one or multiple genes is a significant contributing factor.{{cite journal | vauthors = Ronemus M, Iossifov I, Levy D, Wigler M | title = The role of de novo mutations in the genetics of autism spectrum disorders | journal = Nature Reviews. Genetics | volume = 15 | issue = 2 | pages = 133–41 | date = February 2014 | pmid = 24430941 | doi = 10.1038/nrg3585 | s2cid = 9073763 }} Tens of individual genes or mutations have been definitively identified and are cataloged by the Simons Foundation Autism Research Initiative.{{cite web|title=SFARI CNV|url=https://gene.sfari.org/autdb/CNVHome.do|access-date=2016-03-19|archive-date=2016-03-29|archive-url=https://web.archive.org/web/20160329000135/https://gene.sfari.org/autdb/CNVHome.do}}{{cite web|title=SFARI gene scoring module|url=https://gene.sfari.org/autdb/GS_Home.do|access-date=2016-03-19|archive-date=2016-03-28|archive-url=https://web.archive.org/web/20160328212048/https://gene.sfari.org/autdb/GS_Home.do}}

Examples of autism that has arisen from a rare or de novo mutation in a single-gene or locus include neurodevelopmental disorders like fragile X syndrome; metabolic conditions (for example, propionic acidemia);{{Cite journal |last=Shchelochkov |first=Oleg A. |last2=Farmer |first2=Cristan A. |last3=Chlebowski |first3=Colby |last4=Adedipe |first4=Dee |last5=Ferry |first5=Susan |last6=Manoli |first6=Irini |last7=Pass |first7=Alexandra |last8=McCoy |first8=Samantha |last9=Van Ryzin |first9=Carol |last10=Sloan |first10=Jennifer |last11=Thurm |first11=Audrey |last12=Venditti |first12=Charles P. |date=2024-01-11 |title=Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology |url=https://www.nature.com/articles/s41380-023-02385-5 |journal=Molecular Psychiatry |language=en |pages=1–8 |doi=10.1038/s41380-023-02385-5 |issn=1476-5578|doi-access=free |pmc=11176071 }} and chromosomal disorders like 22q13 deletion syndrome and 16p11.2 deletion syndrome.{{cite journal | vauthors = Levitt P, Campbell DB | title = The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders | journal = The Journal of Clinical Investigation | volume = 119 | issue = 4 | pages = 747–54 | date = April 2009 | pmid = 19339766 | pmc = 2662567 | doi = 10.1172/JCI37934 }}

File:Single Chromosome Mutations.svg that have been implicated in autism.]]

These mutations themselves are characterized by considerable variability in clinical outcome and typically only a subset of mutation carriers meet criteria for autism. For example, carriers of the 16p11.2 deletion have a mean IQ 32 points lower than their first-degree relatives that do not carry the deletion, however only 20% are below the threshold IQ of 70 for intellectual disability, and only 20% have autism.{{cite journal | 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 | display-authors = 6 | 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 = 332–41 | date = May 2010 | pmid = 19914906 | pmc = 3158566 | doi = 10.1136/jmg.2009.073015 }}{{cite journal | vauthors = Moreno-De-Luca A, Myers SM, Challman TD, Moreno-De-Luca D, Evans DW, Ledbetter DH | title = Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence | journal = The Lancet. Neurology | volume = 12 | issue = 4 | pages = 406–14 | date = April 2013 | pmid = 23518333 | pmc = 4013791 | doi = 10.1016/S1474-4422(13)70011-5 }} Around 85% have a neurobehavioral diagnosis, including autism, ADHD, anxiety disorders, mood disorders, gross motor delay, and epilepsy, while 15% have no diagnosis. Alongside these neurobehavioral phenotypes, the 16p11.2 deletions / duplications have been associated with macrocephaly / microcephaly, body weight regulation, and the duplication in particular is associated with schizophrenia.{{cite journal | vauthors = McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J | display-authors = 6 | title = Microduplications of 16p11.2 are associated with schizophrenia | journal = Nature Genetics | volume = 41 | issue = 11 | pages = 1223–7 | date = November 2009 | pmid = 19855392 | pmc = 2951180 | doi = 10.1038/ng.474 }}{{cite journal | title = Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders | journal = Neuron | volume = 73 | issue = 6 | pages = 1063–7 | date = March 2012 | pmid = 22445335 | doi = 10.1016/j.neuron.2012.02.014 | author = The Simons Vip Consortium | s2cid = 2687724 | doi-access = free }} Controls that carry mutations associated with autism or schizophrenia typically present with intermediate cognitive phenotypes or fecundity compared to neurodevelopmental cases and population controls.{{cite journal | 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 | display-authors = 6 | title = CNVs conferring risk of autism or schizophrenia affect cognition in controls | journal = Nature | volume = 505 | issue = 7483 | pages = 361–6 | date = January 2014 | pmid = 24352232 | doi = 10.1038/Nature12818 | bibcode = 2014Natur.505..361S | url = http://www.hirsla.lsh.is/lsh/handle/2336/311615 | archive-date = 5 October 2020 | archive-url = https://web.archive.org/web/20201005031108/https://www.hirsla.lsh.is/handle/2336/311615 | hdl = 2336/311615 | s2cid = 3842341 | hdl-access = free }} Therefore, a single mutation can have multiple different effects depending on other genetic and environmental factors.

In this model, autism often arises from a combination of common, functional variants of genes. Each gene contributes a relatively small effect in increasing the risk of autism. In this model, no single gene directly regulates any core symptom of autism such as social behavior. Instead, each gene encodes a protein that disrupts a cellular process, and the combination of these disruptions, possibly together with environmental influences,{{cite journal | vauthors = Wittkowski KM, Sonakya V, Bigio B, Tonn MK, Shic F, Ascano M, Nasca C, Gold-Von Simson G | display-authors = 6 | title = A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism | journal = Translational Psychiatry | volume = 4 | pages = e354 | date = January 2014 | issue = 1 | pmid = 24473445 | pmc = 3905234 | doi = 10.1038/tp.2013.124 }} affect key developmental processes such as synapse formation. For example, one model is that many mutations affect MET and other receptor tyrosine kinases, which in turn converge on disruption of ERK and PI3K signaling.

In this model most families fall into two types: in the majority, sons have a low risk of autism, but in a small minority their risk is near 50%. In the low-risk families, sporadic autism is mainly caused by spontaneous mutation with poor penetrance in daughters and high penetrance in sons. The high-risk families come from (mostly female) children who carry a new causative mutation but are unaffected and transmit the dominant mutation to grandchildren.

{{Main|Epigenetics of autism}}

Several epigenetic models of autism have been proposed.{{cite journal | 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 | display-authors = 6 | 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 | date = November 2004 | pmid = 15389703 | doi = 10.1002/ajmg.a.30297 | s2cid = 9570482 }} These are suggested by the occurrence of autism in individuals with fragile X syndrome, which arises from epigenetic mutations, and with Rett syndrome, which involves epigenetic regulation factors. An epigenetic model would help explain why standard genetic screening strategies have so much difficulty with autism.{{cite journal | vauthors = Schanen NC | title = Epigenetics of autism spectrum disorders | journal = Human Molecular Genetics | volume = 15 | issue = Review 2 | pages = R138-50 | date = October 2006 | pmid = 16987877 | doi = 10.1093/hmg/ddl213 | url = http://hmg.oxfordjournals.org/cgi/content/full/15/suppl_2/R138 | url-status = dead | archive-url = https://web.archive.org/web/20071009192227/http://hmg.oxfordjournals.org/cgi/content/full/15/suppl_2/R138 | archive-date = 2007-10-09 | doi-access = free }}

Genomic imprinting models have been proposed; one of their strengths is explaining the high male-to-female ratio in ASD.{{cite journal | vauthors = Skuse DH | title = Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism | journal = Pediatric Research | volume = 47 | issue = 1 | pages = 9–16 | date = January 2000 | pmid = 10625077 | doi = 10.1203/00006450-200001000-00006 | s2cid = 3140415 | doi-access = free }} One hypothesis is that autism is in some sense diametrically opposite to schizophrenia and other psychotic-spectrum conditions, that alterations of genomic imprinting help to mediate the development of these two sets of conditions, and that ASD involves increased effects of paternally expressed genes, which regulate overgrowth in the brain, whereas schizophrenia involves maternally expressed genes and undergrowth.{{cite journal | vauthors = Crespi B, Badcock C | title = Psychosis and autism as diametrical disorders of the social brain | journal = The Behavioral and Brain Sciences | volume = 31 | issue = 3 | pages = 241–61; discussion 261–320 | date = June 2008 | pmid = 18578904 | doi = 10.1017/S0140525X08004214 | url = http://eprints.lse.ac.uk/21571/1/Psychosis%20and%20autism%20as%20diametrical%20disorders%20of%20the%20social%20brain%20%28LSERO%29.pdf | archive-url = https://web.archive.org/web/20200412200311/http://eprints.lse.ac.uk/21571/1/Psychosis%20and%20autism%20as%20diametrical%20disorders%20of%20the%20social%20brain%20%28LSERO%29.pdf | archive-date = 2020-04-12 }}

Though autism's genetic factors explain most of autism risk, they do not explain all of it. A common hypothesis is that autism is caused by the interaction of a genetic predisposition and an early environmental insult.{{cite journal | vauthors = Trottier G, Srivastava L, Walker CD | title = Etiology of infantile autism: a review of recent advances in genetic and neurobiological research | journal = Journal of Psychiatry & Neuroscience | volume = 24 | issue = 2 | pages = 103–15 | date = March 1999 | pmid = 10212552 | pmc = 1188990 }} Several theories based on environmental factors have been proposed to address the remaining risk. Some of these theories focus on prenatal environmental factors, such as agents that cause birth defects; others focus on the environment after birth, such as children's diets. All known teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight weeks from conception, strong evidence that autism arises very early in development.{{cite journal | vauthors = Arndt TL, Stodgell CJ, Rodier PM | title = The teratology of autism | journal = International Journal of Developmental Neuroscience | volume = 23 | issue = 2–3 | pages = 189–99 | date = 2005 | pmid = 15749245 | doi = 10.1016/j.ijdevneu.2004.11.001 | s2cid = 17797266 }} Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies,{{cite journal | vauthors = Rutter M | title = Incidence of autism spectrum disorders: changes over time and their meaning | journal = Acta Paediatrica | volume = 94 | issue = 1 | pages = 2–15 | date = January 2005 | pmid = 15858952 | doi = 10.1111/j.1651-2227.2005.tb01779.x | s2cid = 79259285 | author-link = Professor Sir Michael Rutter }} extensive searches are underway.{{cite journal | vauthors = Szpir M | title = Tracing the origins of autism: a spectrum of new studies | journal = Environmental Health Perspectives | volume = 114 | issue = 7 | pages = A412-8 | date = July 2006 | pmid = 16835042 | pmc = 1513312 | doi = 10.1289/ehp.114-a412 | url = http://www.ehponline.org/members/2006/114-7/focus.html | url-status = dead | archive-url = https://web.archive.org/web/20080708201740/http://www.ehponline.org/members/2006/114-7/focus.html | archive-date = 2008-07-08 }} A 2015 study has found evidence that non-shared environmental factors has an influence on social impairments in ASD{{Cite journal |last=Deng |first=Wenlin |last2=Zou |first2=Xiaobing |last3=Deng |first3=Hongzhu |last4=Li |first4=Jianying |last5=Tang |first5=Chun |last6=Wang |first6=Xueqin |last7=Guo |first7=Xiaobo |date=November 2015 |title=The Relationship Among Genetic Heritability, Environmental Effects, and Autism Spectrum Disorders: 37 Pairs of Ascertained Twin Study |url=https://journals.sagepub.com/doi/10.1177/0883073815580645 |journal=Journal of Child Neurology |language=en |volume=30 |issue=13 |pages=1794–1799 |doi=10.1177/0883073815580645 |issn=0883-0738}}

Autism spectrum disorder affects all races, ethnicities, and socioeconomic groups. Still, more males than females are affected across all cultures,{{Cite journal|date=2020-04-13 |title=Gene linked to sex differences in autism |url=https://www.nih.gov/news-events/nih-research-matters/gene-linked-sex-differences-autism |access-date=2022-02-28 |journal= NIH Research Matters|department =National Institutes of Health (NIH)| archive-url =https://web.archive.org/web/20220609115003/https://www.nih.gov/news-events/nih-research-matters/gene-linked-sex-differences-autism |archive-date = 2022-06-09 | publisher = U.S. Department of Health and Human Services |language=EN}} the ratios of males-to-females is appropriately 3 to 1.{{cite journal | vauthors = Loomes R, Hull L, Mandy WP | title = What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 56 | issue = 6 | pages = 466–474 | date = June 2017 | pmid = 28545751 | doi = 10.1016/j.jaac.2017.03.013 | s2cid = 20420861 | url = https://discovery.ucl.ac.uk/id/eprint/1558343/ }} A study analyzed the Autism Genetics Resource Exchange ([https://www.autismspeaks.org/agre AGRE database]), which holds resources, research, and records of autism spectrum disorder diagnosis. In this study, it was concluded that when a spontaneous mutation causes autism spectrum disorder (ASD), there is high penetrance in males and low penetrance in females.{{cite journal | vauthors = Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, Law P, Qiu S, Lord C, Sebat J, Ye K, Wigler M | display-authors = 6 | title = A unified genetic theory for sporadic and inherited autism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 31 | pages = 12831–12836 | date = July 2007 | pmid = 17652511 | pmc = 1933261 | doi = 10.1073/pnas.0705803104 | doi-access = free | bibcode = 2007PNAS..10412831Z }} A study published in 2020 explored the reason behind this idea further.{{cite journal | vauthors = Nguyen TA, Wu K, Pandey S, Lehr AW, Li Y, Bemben MA, Badger JD, Lauzon JL, Wang T, Zaghloul KA, Thurm A, Jain M, Lu W, Roche KW | display-authors = 6 | title = A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y | journal = Neuron | volume = 106 | issue = 5 | pages = 759–768.e7 | date = June 2020 | pmid = 32243781 | pmc = 7491604 | doi = 10.1016/j.neuron.2020.03.008 }} It is commonly known that the main difference between males and females is the fact that males have one X and one Y sex chromosome whereas female have two X chromosomes. This leads to the idea that there is a gene on the X chromosome that is not on the Y that is involved with the sex bias of ASD.

In another study, it has been found that the gene called NLGN4, when mutated, can cause ASD.{{cite journal | vauthors = Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T | display-authors = 6 | title = Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism | journal = Nature Genetics | volume = 34 | issue = 1 | pages = 27–29 | date = May 2003 | pmid = 12669065 | pmc = 1925054 | doi = 10.1038/ng1136 }} This gene and other NLGN genes are important for neuron communications. This NLGN4 gene is found on both the X (NLGN4X) and the Y (NLGN4Y) chromosome. The sex chromosomes are 97% identical. It has been determined that most of the mutations that occur are located on the NLGN4X gene. Research into the differences between NLGN4X and NLGN4Y found that the NLGN4Y protein has poor surface expectations and poor synapses regulations, leading to poor neuron communication. Researchers concluded that males have a higher incidence of autism when the mechanism is NLGN4X-associated. This association was concluded since females have two X chromosomes; if there is a mutation in a gene on an X chromosome, the other X chromosome can be used to compensate for the mutation. Whereas males have only one X chromosome, meaning that if there is a mutation in a gene on an X chromosome, then that is the only copy of the gene and it will be used. The genomic difference between males and females is one mechanism that leads to the higher incidence of ASD in males.

Known genetic syndromes, mutations, and metabolic diseases account for up to 20% of autism cases.{{cite journal | vauthors = Benvenuto A, Manzi B, Alessandrelli R, Galasso C, Curatolo P | title = Recent advances in the pathogenesis of syndromic autisms | journal = International Journal of Pediatrics | volume = 2009 | issue = | pages = 198736 | year = 2009 | pmid = 19946417 | pmc = 2778501 | doi = 10.1155/2009/198736 | doi-access = free }} A number of alleles have been shown to have strong linkage to the autism phenotype. In many cases the findings are inconclusive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of genotypes that are

manifested as the autism phenotype. At least some of the alleles associated with autism are fairly prevalent in the general population, which indicates they are not rare pathogenic mutations. This also presents some challenges in identifying all the rare allele combinations involved in the etiology of autism.

A 2008 study compared genes linked with autism to those of other neurological diseases, and found that more than half of known autism genes are implicated in other disorders, suggesting that the other disorders may share molecular mechanisms with autism.{{cite journal | vauthors = Wall DP, Esteban FJ, Deluca TF, Huyck M, Monaghan T, Velez de Mendizabal N, Goñí J, Kohane IS | display-authors = 6 | title = Comparative analysis of neurological disorders focuses genome-wide search for autism genes | journal = Genomics | volume = 93 | issue = 2 | pages = 120–9 | date = February 2009 | pmid = 18950700 | doi = 10.1016/j.ygeno.2008.09.015 | doi-access = free }}

There is a large number of other candidate loci which either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes.{{cite journal | vauthors = Ylisaukko-oja T, Alarcón M, Cantor RM, Auranen M, Vanhala R, Kempas E, von Wendt L, Järvelä I, Geschwind DH, Peltonen L | display-authors = 6 | title = Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families | journal = Annals of Neurology | volume = 59 | issue = 1 | pages = 145–55 | date = January 2006 | pmid = 16288458 | doi = 10.1002/ana.20722 | s2cid = 23223861 }}{{cite journal | vauthors = Lauritsen MB, Als TD, Dahl HA, Flint TJ, Wang AG, Vang M, Kruse TA, Ewald H, Mors O | display-authors = 6 | title = A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands | journal = Molecular Psychiatry | volume = 11 | issue = 1 | pages = 37–46 | date = January 2006 | pmid = 16205737 | doi = 10.1038/sj.mp.4001754 | s2cid = 1318464 | doi-access = free }}{{cite journal | vauthors = Trikalinos TA, Karvouni A, Zintzaras E, Ylisaukko-oja T, Peltonen L, Järvelä I, Ioannidis JP | title = A heterogeneity-based genome search meta-analysis for autism-spectrum disorders | journal = Molecular Psychiatry | volume = 11 | issue = 1 | pages = 29–36 | date = January 2006 | pmid = 16189507 | doi = 10.1038/sj.mp.4001750 | s2cid = 7738080 | doi-access = free }}

A few examples of loci that have been studied are the 17q21 region,{{cite journal | vauthors = Yonan AL, Alarcón M, Cheng R, Magnusson PK, Spence SJ, Palmer AA, Grunn A, Juo SH, Terwilliger JD, Liu J, Cantor RM, Geschwind DH, Gilliam TC | display-authors = 6 | title = A genomewide screen of 345 families for autism-susceptibility loci | journal = American Journal of Human Genetics | volume = 73 | issue = 4 | pages = 886–97 | date = October 2003 | pmid = 13680528 | pmc = 1180610 | doi = 10.1086/378778 }}{{cite journal | vauthors = Cantor RM, Kono N, Duvall JA, Alvarez-Retuerto A, Stone JL, Alarcón M, Nelson SF, Geschwind DH | display-authors = 6 | title = Replication of autism linkage: fine-mapping peak at 17q21 | journal = American Journal of Human Genetics | volume = 76 | issue = 6 | pages = 1050–6 | date = June 2005 | pmid = 15877280 | pmc = 1196442 | doi = 10.1086/430278 }} the 3p24-26 locus, PTEN,{{cite journal | vauthors = Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C | display-authors = 6 | title = Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations | journal = Journal of Medical Genetics | volume = 42 | issue = 4 | pages = 318–21 | date = April 2005 | pmid = 15805158 | pmc = 1736032 | doi = 10.1136/jmg.2004.024646 }} 15q11.2–q13 and deletion in the 22q11.2 area.{{cite news|url=https://spectrumnews.org/opinion/viewpoint/dna-deletion-paves-paths-autism-schizophrenia/|title=Same DNA deletion paves paths to autism, schizophrenia| vauthors = Bearden C |date=2016-10-18|work=|newspaper=Spectrum|language=en-US|access-date=2016-10-18 |archive-date=2016-11-02|archive-url=https://web.archive.org/web/20161102082822/https://spectrumnews.org/opinion/viewpoint/dna-deletion-paves-paths-autism-schizophrenia/}}

Homozygosity mapping in pedigrees with shared ancestry and autism incidence has recently implicated the following candidate genes: PCDH10, DIA1 (formerly known as C3ORF58), NHE9, CNTN3, SCN7A, and RNF8. Several of these genes appeared to be targets of MEF2,{{cite journal | vauthors = Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA | display-authors = 6 | title = Identifying autism loci and genes by tracing recent shared ancestry | journal = Science | volume = 321 | issue = 5886 | pages = 218–23 | date = July 2008 | pmid = 18621663 | pmc = 2586171 | doi = 10.1126/science.1157657 | bibcode = 2008Sci...321..218M }}{{cite journal | vauthors = Geschwind DH | title = Autism: Family connections | journal = Nature | volume = 454 | issue = 7206 | pages = 838–9 | date = August 2008 | pmid = 18704077 | pmc = 3645842 | doi = 10.1038/454838a | bibcode = 2008Natur.454..838G }} one of the transcription factors known to be regulated by neuronal activity{{cite journal | vauthors = Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y, Paradis S, Griffith EC, Hu LS, Chen C, Greenberg ME | display-authors = 6 | title = Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number | journal = Science | volume = 311 | issue = 5763 | pages = 1008–12 | date = February 2006 | pmid = 16484497 | doi = 10.1126/science.1122511 | bibcode = 2006Sci...311.1008F | s2cid = 13280518 }} and that itself has also recently been implicated as an autism-related disorder candidate gene.{{cite journal | vauthors = Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, Soussou W, Nie Z, Kang YJ, Nakanishi N, Okamoto S, Roberts AJ, Schwarz JJ, Lipton SA | display-authors = 6 | title = Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 27 | pages = 9397–402 | date = July 2008 | pmid = 18599437 | pmc = 2453715 | doi = 10.1073/pnas.0802876105 | bibcode = 2008PNAS..105.9397L | doi-access = free }}

{{reflist}}

{{refbegin}}

• {{cite journal | vauthors = O'Roak BJ, State MW | title = Autism genetics: strategies, challenges, and opportunities | journal = Autism Research | volume = 1 | issue = 1 | pages = 4–17 | date = February 2008 | pmid = 19360646 | doi = 10.1002/aur.3 | s2cid = 205457022 | doi-access = free }} An excellent summary of the state and possible future directions of autism genetics research as of late 2007.
• {{cite journal | vauthors = Fisch GS | title = Syndromes and epistemology II: is autism a polygenic disorder? | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 17 | pages = 2203–12 | date = September 2008 | pmid = 18666231 | doi = 10.1002/ajmg.a.32438 | s2cid = 28598067 }} Advocates common disease rare allele (CDRA) over polygenic approaches.
• {{cite journal | vauthors = Losh M, Sullivan PF, Trembath D, Piven J | title = Current developments in the genetics of autism: from phenome to genome | journal = Journal of Neuropathology & Experimental Neurology |issn = 0022-3069 |eissn = 1554-6578 |lccn = 45003177 | oclc = 771166656 |volume = 67 | issue = 9 | pages = 829–37 | date = September 2008 | pmid = 18716561 | pmc = 2649757 | doi = 10.1097/NEN.0b013e318184482d }} Focuses on attempts to match genes to behavior.

{{refend}}

• [http://agre.org/ Autism Genetic Resource Exchange (AGRE)] – 'the world's first collaborative gene bank for autism'

{{Pervasive developmental disorders}}

{{Autism resources}}

Category:Genetics of autism

Category:Medical genetics

Category:Biological psychiatry

Category:Behavioral neuroscience