Genetics of obesity

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Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors.[1][2] 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.[3][4]

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%.[5] 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.[6] The involvement of genetic factors in the development of obesity is estimated to be 40–70%. Some of these obesogenic or leptogenic genes may influence the obese individual's response to weight loss or weight management.[7]

Genes

A painting of a dark haired pink cheeked obese nude young female leaning against a table. She is holding grapes and grape leaves in her left hand which cover her genitalia.
A 1680 painting by Juan Carreño de Miranda of a girl presumed to have Prader-Willi syndrome[8]

Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity.[9][10][11] Many candidate genes are highly expressed in the central nervous system.[12]

Several additional loci have been identified.[13] Also, several quantitative trait loci for BMI have been identified.

Confirmed and hypothesized associations include:

Condition OMIM Locus Notes
leptin deficiency 164160 7q31.3
leptin receptor deficiency 601007 1p31
prohormone convertase-1 deficiency 600955 5q15-q21
proopiomelanocortin deficiency 609734 2p23.3
melanocortin-4 receptor polymorphism (MC4R[14]) 155541 18q22
BMIQ1 7q32.3 near D7S1804[15]
BMIQ2 13q14 near D13S257[15]
BMIQ3 6q23-q25 near D6S1009, GATA184A08, D6S2436, and D6S305[16]
BMIQ4 11q24 near D11S1998, D11S4464, and D11S912[16]
BMIQ5 16p13 near ATA41E04[17]
BMIQ6 20pter-p11.2 near D20S482[17]
INSIG2[14] 2q14.1
FTO[14] 16q12.2 Adults who were homozygous for a particular FTO allele weighed about 3 kilograms more and had a 1.6-fold greater rate of obesity than those who had not inherited this trait.[18] This association disappeared, though, when those with FTO polymorphisms participated in moderately intensive physical activity equivalent to three to four hours of brisk walking.[19]
TMEM18[14] 2p25.3
GNPDA2[14] 4p13
NEGR1[14] 1p31.1
BDNF[14] 11p13
KCTD15[14] 19q13.12 KCTD15 plays a role in transcriptional repression of AP-2α, which in turn, inhibits the activity of C/EBPα, an early inducer of adipogenesis.[20]
KLF14[21]  ? Although it does not play a role in the formation of fat itself, it does determine the location on the body where this fat is stored.
SH2B1[22] 16p11.2
MTCH2[22] 11p11.2
PCSK1[22] 5q15-q21
NPC1[23] 18q11-q12
LYPLAL1[24] 616548 Archived 2022-06-07 at the Wayback Machine 1q41 Disputed metabolic function of being either a lipase[25] or a short-chain carboxylesterase.[26]

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 to less than 10% of the offspring of two parents who were of normal weight.[27]

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.[28] 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.[29]

Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.[30][31]

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.[32]

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.[33][34] Other candidate anti-obesity-related genes include ALK,[35] TBC1D1,[36] and SRA1.[37]

Genetic syndromes

The term "non-syndromic obesity" is sometimes used to exclude these conditions.[38] 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.[39]

See also

Related:

  • Human genetic variation

References

  1. ↑ Albuquerque D, Stice E, et al. (Mar 2015). "Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective". Mol. Genet. Genomics. 290 (4): 1191–221. doi:10.1007/s00438-015-1015-9. hdl:10316/45814. PMID 25749980. S2CID 3238210.
  2. ↑ Albuquerque, David; Nóbrega, Clévio; Manco, Licínio; Padez, Cristina (7 July 2017). "The contribution of genetics and environment to obesity". British Medical Bulletin. Advance articles (1): 159–173. doi:10.1093/bmb/ldx022. PMID 28910990.
  3. ↑ Kushner, Robert (2007). Treatment of the Obese Patient (Contemporary Endocrinology). Totowa, NJ: Humana Press. p. 158. ISBN 978-1-59745-400-1. Archived from the original on January 7, 2017. Retrieved April 5, 2009.
  4. ↑ Adams JP, Murphy PG (July 2000). "Obesity in anaesthesia and intensive care". Br J Anaesth. 85 (1): 91–108. doi:10.1093/bja/85.1.91. PMID 10927998.
  5. ↑ Yang W, Kelly T, He J (2007). "Genetic epidemiology of obesity". Epidemiol Rev. 29: 49–61. doi:10.1093/epirev/mxm004. PMID 17566051.
  6. ↑ Poirier P, Giles TD, Bray GA, et al. (May 2006). "Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss". Arterioscler. Thromb. Vasc. Biol. 26 (5): 968–76. CiteSeerX 10.1.1.508.7066. doi:10.1161/01.ATV.0000216787.85457.f3. PMID 16627822. S2CID 6052584.
  7. ↑ Hainer, Vojtĕch; Hermann Toplak; Asimina Mitrakou (February 2008). "Treatment Modalities of Obesity: What fits whom?". Diabetes Care. 31: 269–277. doi:10.2337/dc08-s265. PMID 18227496.
  8. ↑ Mary Jones. "Case Study: Cataplexy and SOREMPs Without Excessive Daytime Sleepiness in Prader Willi Syndrome. Is This the Beginning of Narcolepsy in a Five Year Old?". European Society of Sleep Technologists. Archived from the original on June 6, 2017. Retrieved April 6, 2009.
  9. ↑ Lee YS (January 2009). "The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature" (PDF). Ann. Acad. Med. Singap. 38 (1): 34–44. PMID 19221669. Archived from the original (PDF) on 2011-07-21. Retrieved 2009-06-08.
  10. ↑ "Researchers discover DNA variants significantly influence body fat distribution". medicalxpress.com. Archived from the original on 2019-02-18. Retrieved 2019-03-12.
  11. ↑ Lindgren, Cecilia M.; North, Kari E.; Loos, Ruth J. F.; Cupples, L. Adrienne; Hirschhorn, Joel N.; Kutalik, Zoltán; Rotter, Jerome I.; Mohlke, Karen L.; Lettre, Guillaume (18 February 2019). "Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution". Nature Genetics. 51 (3): 452–469. doi:10.1038/s41588-018-0334-2. ISSN 1546-1718. PMC 6560635. PMID 30778226.
  12. ↑ Willer CJ, Speliotes EK, Loos RJ, et al. (January 2009). "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation". Nat. Genet. 41 (1): 25–34. doi:10.1038/ng.287. PMC 2695662. PMID 19079261.
  13. ↑ "OMIM - OBESITY". Archived from the original on 2015-07-22. Retrieved 2009-06-08.
  14. 1 2 3 4 5 6 7 8 Zhao J, Bradfield JP, Li M, et al. (May 2009). "The role of obesity-associated loci identified in genome wide association studies in the determination of pediatric BMI". Obesity (Silver Spring). 17 (12): 2254–7. doi:10.1038/oby.2009.159. PMC 2860782. PMID 19478790.
  15. 1 2 Feitosa MF, Borecki IB, Rich SS, et al. (January 2002). "Quantitative-Trait Loci Influencing Body-Mass Index Reside on Chromosomes 7 and 13: The National Heart, Lung, and Blood Institute Family Heart Study". Am. J. Hum. Genet. 70 (1): 72–82. doi:10.1086/338144. PMC 384905. PMID 11713718.
  16. 1 2 Atwood LD, Heard-Costa NL, Cupples LA, Jaquish CE, Wilson PW, D'Agostino RB (November 2002). "Genomewide Linkage Analysis of Body Mass Index across 28 Years of the Framingham Heart Study". Am. J. Hum. Genet. 71 (5): 1044–50. doi:10.1086/343822. PMC 385083. PMID 12355400.
  17. 1 2 Gorlova OY, Amos CI, Wang NW, Shete S, Turner ST, Boerwinkle E (June 2003). "Genetic linkage and imprinting effects on body mass index in children and young adults". Eur. J. Hum. Genet. 11 (6): 425–32. doi:10.1038/sj.ejhg.5200979. PMID 12774034.
  18. ↑ Frayling TM, Timpson NJ, Weedon MN, et al. (2007). "A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity". Science. 316 (5826): 889–94. doi:10.1126/science.1141634. PMC 2646098. PMID 17434869.
  19. ↑ Rampersaud E, Mitchell BD, Pollin TI, et al. (2008). "Physical activity and the association of common FTO gene variants with body mass index and obesity". Arch Intern Med. 168 (16): 1791–97. doi:10.1001/archinte.168.16.1791. PMC 3635949. PMID 18779467.
  20. ↑ Skoblov, Mikhail; Andrey Marakhonov; Ekaterina Marakasova; Anna Guskova; Vikas Chandhoke; Aybike Birerdinc; Ancha Baranova (2013). "Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development". BioEssays. 35 (7): 586–596. doi:10.1002/bies.201300002. PMID 23592240.
  21. ↑ Small KS, Hedman AK, Grundberg E, et al. (June 2011). "Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes". Nat. Genet. 43 (6): 561–4. doi:10.1038/ng.833. PMC 3192952. PMID 21572415.
  22. 1 2 3 Renström F, Payne F, Nordström A, et al. (April 2009). "Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden". Hum. Mol. Genet. 18 (8): 1489–96. doi:10.1093/hmg/ddp041. PMC 2664142. PMID 19164386.
  23. ↑ Meyre, David; Delplanque, Jérôme; Chèvre, Jean-Claude; Lecoeur, CéCile; Lobbens, StéPhane; Gallina, Sophie; Durand, Emmanuelle; Vatin, Vincent; et al. (18 January 2009). "Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations". Nature Genetics. 41 (2): 157–9. doi:10.1038/ng.301. PMID 19151714. S2CID 11218794.
  24. ↑ Heid, Iris M.; Jackson, Anne U.; Randall, Joshua C.; Winkler, Thomas W.; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M. Carola; Speliotes, Elizabeth K. (November 2010). "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution". Nature Genetics. 42 (11): 949–960. doi:10.1038/ng.685. ISSN 1546-1718. PMC 3000924. PMID 20935629.
  25. ↑ Steinberg, Gregory R.; Kemp, Bruce E.; Watt, Matthew J. (October 2007). "Adipocyte triglyceride lipase expression in human obesity". American Journal of Physiology. Endocrinology and Metabolism. 293 (4): E958–964. doi:10.1152/ajpendo.00235.2007. ISSN 0193-1849. PMID 17609260.
  26. ↑ Bürger, Marco; Zimmermann, Tobias J.; Kondoh, Yasumitsu; Stege, Patricia; Watanabe, Nobumoto; Osada, Hiroyuki; Waldmann, Herbert; Vetter, Ingrid R. (January 2012). "Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases". Journal of Lipid Research. 53 (1): 43–50. doi:10.1194/jlr.M019851. ISSN 1539-7262. PMC 3243480. PMID 22052940.
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  28. ↑ Chakravarthy MV, Booth FW (2004). "Eating, exercise, and "thrifty" genotypes: Connecting the dots toward an evolutionary understanding of modern chronic diseases". J. Appl. Physiol. 96 (1): 3–10. doi:10.1152/japplphysiol.00757.2003. PMID 14660491.
  29. ↑ Wells JC (February 2009). "Ethnic variability in adiposity and cardiovascular risk: the variable disease selection hypothesis". Int J Epidemiol. 38 (1): 63–71. doi:10.1093/ije/dyn183. PMID 18820320.
  30. ↑ Garland Jr, Theodore; Schutz, Heidi; Chappell, Mark A.; Keeney, Brooke K.; Meek, Thomas H.; Copes, Lynn E.; Acosta, Wendy; Drenowatz, Clemens; Maciel, Robert C.; van Dijk, Gertjan; Kotz, Catherine M.; Eisenmann, Joey C. (2011). "The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives". J. Exp. Biol. 214 (2): 206–29. doi:10.1242/jeb.048397. PMC 3008631. PMID 21177942.
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  32. ↑ Yang, Wenjie; Tanika Kelly; Jiang He (June 12, 2007). "Genetic Epidemiology of Obesity". Epidemiologic Reviews. 29: 49–61. doi:10.1093/epirev/mxm004. PMID 17566051.
  33. ↑ "Gene variants related to controlling body weight isolated". medicalxpress.com. Archived from the original on 14 August 2021. Retrieved 14 August 2021.
  34. ↑ Akbari, Parsa; et al. (2 July 2021). "Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity". Science. 373 (6550): eabf8683. doi:10.1126/science.abf8683. ISSN 0036-8075. PMID 34210852. S2CID 235699731. Archived from the original on 24 August 2021. Retrieved 23 February 2022.
  35. ↑ Orthofer, Michael; Valsesia, Armand; Mägi, Reedik; Wang, Qiao-Ping; Kaczanowska, Joanna; Kozieradzki, Ivona; Leopoldi, Alexandra; Cikes, Domagoj; Zopf, Lydia M.; Tretiakov, Evgenii O.; Demetz, Egon; Hilbe, Richard; Boehm, Anna; Ticevic, Melita; Nõukas, Margit; Jais, Alexander; Spirk, Katrin; Clark, Teleri; Amann, Sabine; Lepamets, Maarja; Neumayr, Christoph; Arnold, Cosmas; Dou, Zhengchao; Kuhn, Volker; Novatchkova, Maria; Cronin, Shane J. F.; Tietge, Uwe J. F.; Müller, Simone; Pospisilik, J. Andrew; Nagy, Vanja; Hui, Chi-Chung; Lazovic, Jelena; Esterbauer, Harald; Hagelkruys, Astrid; Tancevski, Ivan; Kiefer, Florian W.; Harkany, Tibor; Haubensak, Wulf; Neely, G. Gregory; Metspalu, Andres; Hager, Jorg; Gheldof, Nele; Penninger, Josef M. (11 June 2020). "Identification of ALK in Thinness". Cell. 181 (6): 1246–1262.e22. doi:10.1016/j.cell.2020.04.034. ISSN 0092-8674. PMID 32442405.
  36. ↑ Chadt, Alexandra; Leicht, Katja; Deshmukh, Atul; Jiang, Lake Q.; Scherneck, Stephan; Bernhardt, Ulrike; Dreja, Tanja; Vogel, Heike; Schmolz, Katja; Kluge, Reinhart; Zierath, Juleen R.; Hultschig, Claus; Hoeben, Rob C.; Schürmann, Annette; Joost, Hans-Georg; Al-Hasani, Hadi (November 2008). "Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity". Nature Genetics. 40 (11): 1354–1359. doi:10.1038/ng.244. ISSN 1546-1718. PMID 18931681. S2CID 4069428.
  37. ↑ Liu, Shannon; Sheng, Liang; Miao, Hongzhi; Saunders, Thomas L.; MacDougald, Ormond A.; Koenig, Ronald J.; Xu, Bin (May 2014). "SRA Gene Knockout Protects against Diet-induced Obesity and Improves Glucose Tolerance". Journal of Biological Chemistry. 289 (19): 13000–13009. doi:10.1074/jbc.M114.564658. PMC 4036315. PMID 24675075.
  38. ↑ Walley AJ, Asher JE, Froguel P (June 2009). "The genetic contribution to non-syndromic human obesity". Nat. Rev. Genet. 10 (7): 431–42. doi:10.1038/nrg2594. PMID 19506576. S2CID 10870369.
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