Genetics of obesity
{{Short description|Relation between obesity and genetic factors}}
File:La monstrua desnuda (1680), de Juan Carreño de Miranda..jpg of a girl presumed to have Prader-Willi syndrome{{cite web |url=http://www.esst.org/newsletter2000.htm |title=Case Study: Cataplexy and SOREMPs Without Excessive Daytime Sleepiness in Prader Willi Syndrome. Is This the Beginning of Narcolepsy in a Five Year Old?|author=Mary Jones|publisher=European Society of Sleep Technologists|access-date=April 6, 2009}}]]
{{Human body weight}}
Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors.{{cite journal |vauthors=Albuquerque D, Stice E, etal |title= Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective |journal=Mol. Genet. Genomics |date=Mar 2015 |pmid= 25749980 |doi=10.1007/s00438-015-1015-9 |volume=290 |issue= 4 |pages=1191–221|hdl= 10316/45814 |s2cid= 3238210 |hdl-access=free }}{{cite journal |last1=Albuquerque |first1=David |last2=Nóbrega |first2=Clévio |last3=Manco |first3=Licínio |last4=Padez |first4=Cristina |date=7 July 2017 |title=The contribution of genetics and environment to obesity |journal=British Medical Bulletin |volume=Advance articles |issue= 1|pages=159–173 |doi=10.1093/bmb/ldx022|pmid=28910990 |doi-access=free }} Studies have identified variants in several genes that may contribute to weight gain and body fat distribution, although only in a few cases are genes the primary cause of obesity.{{cite book|author=Kushner, Robert |title=Treatment of the Obese Patient (Contemporary Endocrinology) |publisher=Humana Press |location=Totowa, NJ |year=2007 |page=158 |isbn=978-1-59745-400-1 |url=https://books.google.com/books?id=vWjK5etS7PMC |access-date=April 5, 2009}}{{cite journal |vauthors=Adams JP, Murphy PG | title = Obesity in anaesthesia and intensive care | journal = Br J Anaesth | volume = 85 | issue = 1 | pages = 91–108 | date = July 2000 | pmid = 10927998 | doi = 10.1093/bja/85.1.91 | doi-access = free }} Recent research indicates that environmental influences can lead to epigenetic modifications affecting gene expression related to obesity. These changes can alter metabolic processes and appetite regulation, contributing to obesity development.{{Citation |last=Bheda |first=Poonam |title=Aging-associated changes in metabolic regulation of epigenetic modifications and gene expression |date=2021 |work=Epigenetics and Metabolomics |pages=75–95 |url=https://doi.org/10.1016/b978-0-323-85652-2.00006-3 |access-date=2025-03-24 |publisher=Elsevier |doi=10.1016/b978-0-323-85652-2.00006-3 |isbn=978-0-323-85652-2}}
Polymorphisms in various genes controlling appetite and metabolism predispose to obesity under certain dietary conditions. The percentage of obesity that can be attributed to genetics varies widely, depending on the population examined, from 6% to 85%,{{cite journal |vauthors=Yang W, Kelly T, He J |title=Genetic epidemiology of obesity |journal=Epidemiol Rev |volume=29 |pages=49–61 |year=2007 |pmid=17566051 |doi=10.1093/epirev/mxm004|doi-access=free }} with the typical estimate at 50%. It is likely that in each person a number of genes contribute to the likelihood of developing obesity in small part, with each gene increasing or decreasing the odds marginally, and together determining how an individual responds to the environmental factors.{{Cite journal |last1=Lyon |first1=Helen N |last2=Hirschhorn |first2=Joel N |date=2005-07-01 |title=Genetics of common forms of obesity: a brief overview |url=https://academic.oup.com/ajcn/article/82/1/215S/4863389 |journal=The American Journal of Clinical Nutrition |language=en |volume=82 |issue=1 |pages=215S–217S |doi=10.1093/ajcn/82.1.215S |issn=0002-9165|doi-access=free }} As of 2006, more than 41 sites on the human genome have been linked to the development of obesity when a favorable environment is present.{{cite journal |vauthors=Poirier P, Giles TD, Bray GA, etal |title=Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss |journal=Arterioscler. Thromb. Vasc. Biol. |volume=26 |issue=5 |pages=968–76 |date=May 2006 |pmid=16627822 |doi=10.1161/01.ATV.0000216787.85457.f3 |citeseerx=10.1.1.508.7066 |s2cid=6052584 }} Some of these obesogenic (weight gain) or [https://en.wiktionary.org/wiki/leptogenic leptogenic] (weight loss) genes may influence the obese individual's response to weight loss or weight management.{{cite journal|last=Hainer|first=Vojtĕch|author2=Hermann Toplak |author3=Asimina Mitrakou |title=Treatment Modalities of Obesity: What fits whom?|journal=Diabetes Care|date=February 2008|volume=31|pages=269–277|doi=10.2337/dc08-s265|pmid=18227496|doi-access=free}}
Epigenetic influences and environmental interactions
Epigenetics plays a critical role in obesity susceptibility.{{Cite web |date=2025-02-03 |title=Epigenetic Transgenerational Inheritance of Obesity Susceptibility - PMC |url=http://web.archive.org/web/20250203041739/https://pmc.ncbi.nlm.nih.gov/articles/PMC8260009/ |access-date=2025-04-20 |website=web.archive.org}} Environmental exposures, such as poor maternal nutrition and exposure to endocrine-disrupting chemicals, can induce epigenetic modifications that alter gene expression without changing the DNA sequence.{{Cite journal |last1=Heianza |first1=Yoriko |last2=Qi |first2=Lu |date=2017-04-07 |title=Gene-Diet Interaction and Precision Nutrition in Obesity |journal=International Journal of Molecular Sciences |volume=18 |issue=4 |pages=787 |doi=10.3390/ijms18040787 |doi-access=free |issn=1422-0067 |pmc=5412371 |pmid=28387720}} Research on epigenetic transgenerational inheritance suggests that environmental insults can reprogram the epigenome of germline cells (sperm and eggs), leading to obesity susceptibility in future generations.
Gene-environment interactions further complicate obesity risk. Certain genetic variants modify an individual's response to dietary intake, physical activity, and other lifestyle factors.{{Cite journal |last1=Heianza |first1=Yoriko |last2=Qi |first2=Lu |date=2017-04-07 |title=Gene-Diet Interaction and Precision Nutrition in Obesity |journal=International Journal of Molecular Sciences |volume=18 |issue=4 |pages=787 |doi=10.3390/ijms18040787 |doi-access=free |issn=1422-0067 |pmc=5412371 |pmid=28387720}} For example, some individuals with specific FTO variants may have an increased appetite and lower satiety, predisposing them to higher caloric intake and weight gain. Conversely, adherence to a healthy diet can significantly reduce the genetic effects on body mass index (BMI), emphasizing the importance of lifestyle modifications even in genetically predisposed individuals.
Specific genetic mechanisms
Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity.{{cite journal|author=Lee YS |title=The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature |journal=Ann. Acad. Med. Singap. |volume=38 |issue=1 |pages=34–44|date=January 2009 |doi=10.47102/annals-acadmedsg.V38N1p34 |pmid=19221669 |s2cid=21049001 |url=http://www.annals.edu.sg/pdf/38VolNo1Jan2009/V38N1p34.pdf |access-date=2009-06-08 |url-status=dead |archive-url=https://web.archive.org/web/20110721001459/http://www.annals.edu.sg/pdf/38VolNo1Jan2009/V38N1p34.pdf |archive-date=2011-07-21 }}{{Cite web|url=https://medicalxpress.com/news/2019-02-dna-variants-significantly-body-fat.html|title=Researchers discover DNA variants significantly influence body fat distribution|website=medicalxpress.com|language=en-us|access-date=2019-03-12}}{{Cite journal|last1=Lindgren|first1=Cecilia M.|last2=North|first2=Kari E.|last3=Loos|first3=Ruth J. F.|last4=Cupples|first4=L. Adrienne|last5=Hirschhorn|first5=Joel N.|last6=Kutalik|first6=Zoltán|last7=Rotter|first7=Jerome I.|last8=Mohlke|first8=Karen L.|last9=Lettre|first9=Guillaume|date=18 February 2019|title=Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution|journal=Nature Genetics|language=en|volume=51|issue=3|pages=452–469|doi=10.1038/s41588-018-0334-2|pmid=30778226|pmc=6560635|issn=1546-1718}} Many candidate genes are highly expressed in the central nervous system.{{cite journal |vauthors=Willer CJ, Speliotes EK, Loos RJ, etal |title=Six new loci associated with body mass index highlight a neuronal influence on body weight regulation |journal=Nat. Genet. |volume=41 |issue=1 |pages=25–34 |date=January 2009 |pmid=19079261 |pmc=2695662 | doi=10.1038/ng.287}} The development of genetic tests, such as MyPhenome, enables the classification of obesity into specific subtypes based on genetic and phenotypic data. This stratification allows for personalized treatment approaches, improving the effectiveness of obesity interventions.{{Cite magazine |last=Park |first=Alice |date=2024-10-30 |title=Phenomix Sciences MyPhenome: the 200 Best Inventions of 2024 |url=https://time.com/7094906/phenomix-sciences-myphenome/ |access-date=2025-03-24 |magazine=TIME |language=en}} Research has identified genes associated with obesity in both humans and animals. For example, the DENND1B gene has been linked to obesity in Labrador retrievers and humans, highlighting shared genetic factors influencing weight gain across species.{{Cite web |last=Correspondent |first=Rhys Blakely, Science |date=2025-03-06 |title=The 'hungry genes' that make labradors — and humans — fat |url=https://www.thetimes.com/uk/science/article/hungry-genes-fat-obesity-labradors-dennd1b-qv3w9g2dr |access-date=2025-03-24 |website=www.thetimes.com |language=en}}
Several additional loci have been identified.{{cite web |url=https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601665 |title=OMIM - OBESITY |access-date=2009-06-08}} Also, several quantitative trait loci for BMI have been identified.
Confirmed and hypothesized associations include:
Some studies have focused upon inheritance patterns without focusing upon specific genes. One study found that 80% of the offspring of two obese parents were obese. In contrast, less than 10% of offspring of two parents who were of normal weight were obese.{{cite book |author=Kolata, Gina |title=Rethinking thin: The new science of weight loss - and the myths and realities of dieting |publisher=Picador |year=2007 |pages=122 |isbn=978-0-312-42785-6}}
The thrifty gene hypothesis postulates that due to dietary scarcity during human evolution people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would more likely survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies.{{cite journal |vauthors=Chakravarthy MV, Booth FW |title=Eating, exercise, and "thrifty" genotypes: Connecting the dots toward an evolutionary understanding of modern chronic diseases |journal=J. Appl. Physiol. |volume=96 |issue=1 |pages=3–10 |year=2004 |pmid=14660491 |doi=10.1152/japplphysiol.00757.2003}} This is the presumed reason that Pima Native Americans, who evolved in a desert ecosystem, developed some of the highest rates of obesity when exposed to a Western lifestyle.{{cite journal |author=Wells JC |title=Ethnic variability in adiposity and cardiovascular risk: the variable disease selection hypothesis |journal=Int J Epidemiol |volume=38 |issue=1 |pages=63–71 |date=February 2009 |pmid=18820320 |doi=10.1093/ije/dyn183 |doi-access=free }} Emerging research suggests that genetic factors may contribute to the common phenomenon of weight regain after weight loss, known as yo-yo dieting. These genetic influences can affect metabolic rate and appetite regulation, making sustained weight loss challenging for some individuals. {{Cite web |last=Bee |first=Peta |date=2024-12-06 |title=Weight loss: The real reasons the pounds creep back on |url=https://www.thetimes.com/life-style/health-fitness/article/why-am-i-not-losing-weight-8b9pwrsp9 |access-date=2025-03-24 |website=www.thetimes.com |language=en}}
Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.{{cite journal |title=The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives |journal=J. Exp. Biol. |volume=214 |pages=206–29 |year=2011 |pmid=21177942 |doi=10.1242/jeb.048397 |issue=2 |pmc=3008631| first1=Theodore | last1=Garland Jr | first2=Heidi | last2=Schutz | first3=Mark A. | last3=Chappell | first4=Brooke K. | last4=Keeney | first5=Thomas H. | last5=Meek | first6=Lynn E. | last6=Copes | first7=Wendy | last7=Acosta | first8=Clemens | last8=Drenowatz | first9=Robert C. | last9=Maciel | first10=Gertjan | last10=van Dijk | first11=Catherine M. | last11=Kotz | first12=Joey C. | last12=Eisenmann |bibcode=2011JExpB.214..206G | author-link1=Theodore Garland }}{{cite journal| pmid=23312289 | doi=10.1016/j.cmet.2012.12.007 | pmc=3545283 | volume=17 | issue=1 | title=Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice | year=2013 |vauthors=Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, Pan C, Civelek M, Rau CD, Bennett BJ, Mehrabian M, Ursell LK, He A, Castellani LW, Zinker B, Kirby M, Drake TA, Drevon CA, Knight R, Gargalovic P, Kirchgessner T, Eskin E, Lusis AJ| journal=Cell Metab | pages=141–52}}
The risk of obesity is determined by not only specific genotypes but also gene-gene interactions. However, there are still challenges associated with detecting gene-gene interactions for obesity.{{cite journal|last=Yang|first=Wenjie|author2=Tanika Kelly |author3=Jiang He |title=Genetic Epidemiology of Obesity|journal=Epidemiologic Reviews|date=June 12, 2007|volume=29|pages=49–61|doi=10.1093/epirev/mxm004|pmid=17566051|doi-access=free}}
= Monogenic and syndromic obesity =
Monogenic obesity results from single-gene mutations that disrupt the body's ability to regulate weight. These cases are rare but often lead to severe early-onset obesity. Studies have identified mutations in genes such as LEP (leptin), LEPR(leptin receptor), MC4R (melanocortin 4 receptor), and POMC (pro-opiomelanocortin), which play crucial roles in appetite regulation and energy balance.{{Cite web |date=2018-01-29 |title=Genomics and Obesity: We Need Both Population and Individualized Approaches in the Prevention and Management of Obesity {{!}} Blogs {{!}} CDC |url=https://blogs.cdc.gov/genomics/2018/01/29/genomics-and-obesity/ |access-date=2025-04-20 |language=en-us}} Syndromic obesity, a subset of monogenic obesity, is associated with additional developmental and endocrine abnormalities, as seen in conditions like Prader-Willi and Bardet-Biedl syndromes. Research suggests that these rare forms of genetic obesity may be more prevalent in severely obese children than previously estimated due to limited genetic screening availability.
= Polygenic obesity =
Polygenic obesity results from the combined effect of multiple genes that individually exert a small influence on body weight. Genome-wide association studies (GWAS) have identified numerous loci associated with obesity susceptibility, including the FTO(fat mass and obesity-associated) and MC4R genes.{{Cite web |date=2018-01-29 |title=Genomics and Obesity: We Need Both Population and Individualized Approaches in the Prevention and Management of Obesity {{!}} Blogs {{!}} CDC |url=https://blogs.cdc.gov/genomics/2018/01/29/genomics-and-obesity/ |access-date=2025-04-20 |language=en-us}} These genes are involved in processes such as appetite regulation, lipid metabolism, and energy homeostasis. Genetic variants in these loci interact with lifestyle factors, influencing an individual’s likelihood of developing obesity.
= Genes protective against obesity =
There are also genes that can be protective against obesity. For instance, in GPR75 variants were identified as such alleles in ~640,000 sequenced exomes which may be relevant to e.g. therapeutic strategies against obesity.{{cite news |title=Gene variants related to controlling body weight isolated |url=https://medicalxpress.com/news/2021-07-gene-variants-body-weight-isolated.html |access-date=14 August 2021 |work=medicalxpress.com |language=en}}{{cite journal |title=Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity |journal=Science |date=2 July 2021 |volume=373 |issue=6550 |doi=10.1126/science.abf8683 |language=en |issn=0036-8075|last1=Akbari |first1=Parsa |last2=Gilani |first2=Ankit |last3=Sosina |first3=Olukayode |last4=Kosmicki |first4=Jack A. |last5=Khrimian |first5=Lori |last6=Fang |first6=Yi-Ya |last7=Persaud |first7=Trikaldarshi |last8=Garcia |first8=Victor |last9=Sun |first9=Dylan |last10=Li |first10=Alexander |last11=Mbatchou |first11=Joelle |last12=Locke |first12=Adam E. |last13=Benner |first13=Christian |last14=Verweij |first14=Niek |last15=Lin |first15=Nan |last16=Hossain |first16=Sakib |last17=Agostinucci |first17=Kevin |last18=Pascale |first18=Jonathan V. |last19=Dirice |first19=Ercument |last20=Dunn |first20=Michael |last21=Kraus |first21=William E. |last22=Shah |first22=Svati H. |last23=Chen |first23=Yii-Der I. |last24=Rotter |first24=Jerome I. |last25=Rader |first25=Daniel J. |last26=Melander |first26=Olle |last27=Still |first27=Christopher D. |last28=Mirshahi |first28=Tooraj |last29=Carey |first29=David J. |last30=Berumen-Campos |first30=Jaime |pages=eabf8683 |pmid=34210852 |s2cid=235699731 |display-authors=1 |pmc=10275396 }} Other candidate anti-obesity-related genes include ALK,{{cite journal |last1=Orthofer |first1=Michael |last2=Valsesia |first2=Armand |last3=Mägi |first3=Reedik |last4=Wang |first4=Qiao-Ping |last5=Kaczanowska |first5=Joanna |last6=Kozieradzki |first6=Ivona |last7=Leopoldi |first7=Alexandra |last8=Cikes |first8=Domagoj |last9=Zopf |first9=Lydia M. |last10=Tretiakov |first10=Evgenii O. |last11=Demetz |first11=Egon |last12=Hilbe |first12=Richard |last13=Boehm |first13=Anna |last14=Ticevic |first14=Melita |last15=Nõukas |first15=Margit |last16=Jais |first16=Alexander |last17=Spirk |first17=Katrin |last18=Clark |first18=Teleri |last19=Amann |first19=Sabine |last20=Lepamets |first20=Maarja |last21=Neumayr |first21=Christoph |last22=Arnold |first22=Cosmas |last23=Dou |first23=Zhengchao |last24=Kuhn |first24=Volker |last25=Novatchkova |first25=Maria |last26=Cronin |first26=Shane J. F. |last27=Tietge |first27=Uwe J. F. |last28=Müller |first28=Simone |last29=Pospisilik |first29=J. Andrew |last30=Nagy |first30=Vanja |last31=Hui |first31=Chi-Chung |last32=Lazovic |first32=Jelena |last33=Esterbauer |first33=Harald |last34=Hagelkruys |first34=Astrid |last35=Tancevski |first35=Ivan |last36=Kiefer |first36=Florian W. |last37=Harkany |first37=Tibor |last38=Haubensak |first38=Wulf |last39=Neely |first39=G. Gregory |last40=Metspalu |first40=Andres |last41=Hager |first41=Jorg |last42=Gheldof |first42=Nele |last43=Penninger |first43=Josef M. |title=Identification of ALK in Thinness |journal=Cell |date=11 June 2020 |volume=181 |issue=6 |pages=1246–1262.e22 |doi=10.1016/j.cell.2020.04.034 |pmid=32442405 |language=English |issn=0092-8674|doi-access=free }} TBC1D1,{{cite journal |last1=Chadt |first1=Alexandra |last2=Leicht |first2=Katja |last3=Deshmukh |first3=Atul |last4=Jiang |first4=Lake Q. |last5=Scherneck |first5=Stephan |last6=Bernhardt |first6=Ulrike |last7=Dreja |first7=Tanja |last8=Vogel |first8=Heike |last9=Schmolz |first9=Katja |last10=Kluge |first10=Reinhart |last11=Zierath |first11=Juleen R. |last12=Hultschig |first12=Claus |last13=Hoeben |first13=Rob C. |last14=Schürmann |first14=Annette |last15=Joost |first15=Hans-Georg |last16=Al-Hasani |first16=Hadi |title=Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity |journal=Nature Genetics |date=November 2008 |volume=40 |issue=11 |pages=1354–1359 |doi=10.1038/ng.244 |pmid=18931681 |s2cid=4069428 |language=en |issn=1546-1718}} and SRA1.{{cite journal |last1=Liu |first1=Shannon |last2=Sheng |first2=Liang |last3=Miao |first3=Hongzhi |last4=Saunders |first4=Thomas L. |last5=MacDougald |first5=Ormond A. |last6=Koenig |first6=Ronald J. |last7=Xu |first7=Bin |title=SRA Gene Knockout Protects against Diet-induced Obesity and Improves Glucose Tolerance |journal=Journal of Biological Chemistry |date=May 2014 |volume=289 |issue=19 |pages=13000–13009 |doi=10.1074/jbc.M114.564658|pmid=24675075 |pmc=4036315 |doi-access=free }}
Genetic syndromes
The term "non-syndromic obesity" is sometimes used to exclude these conditions.{{cite journal |vauthors=Walley AJ, Asher JE, Froguel P |title=The genetic contribution to non-syndromic human obesity |journal=Nat. Rev. Genet. |volume= 10|issue= 7|pages= 431–42|date=June 2009 |pmid=19506576 | doi=10.1038/nrg2594|s2cid=10870369 }} In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single locus mutation.{{cite journal|last1=Farooqi|first1=I. Sadaf|author-link1=Sadaf Farooqi|last2=O’Rahilly|first2=Stephen|author-link2=Stephen O'Rahilly|title=Genetics of Obesity in Humans|journal=Endocrine Reviews|volume=27|issue=7|year=2006|pages=710–718|pmid= 17122358 |doi=10.1210/er.2006-0040|doi-access=free}}
Current and emerging treatments for genetic obesity
The primary management approach for genetic obesity remains lifestyle interventions, including dietary modifications and physical activity. However, emerging therapies are being developed to target specific genetic pathways. For example, leptin replacement therapy has shown efficacy in treating individuals with leptin deficiency, while melanocortin receptor agonists are being investigated for their potential in addressing MC4R-related obesity.{{Cite web |date=2025-02-03 |title=Current Treatments for Patients with Genetic Obesity - PMC |url=http://web.archive.org/web/20250203172101/https://pmc.ncbi.nlm.nih.gov/articles/PMC10234057/ |access-date=2025-04-20 |website=web.archive.org}} Ongoing clinical trials continue to explore novel pharmacological and gene-based therapies that may offer more effective treatment options for individuals with genetic obesity.