Genetics of obesity

Short description: Relation between obesity and genetic factors

A 1680 painting by Juan Carreño de Miranda of a girl presumed to have Prader-Willi syndrome[1]

Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors.[2][3] 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.[4][5]

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%,[6] 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.[7] 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.[8] Some of these obesogenic (weight gain) or leptogenic (weight loss) genes may influence the obese individual's response to weight loss or weight management.[9]

## Contents

* 1 Genes
* 1.1 Genes protective against obesity
* 2 Genetic syndromes
* 3 See also
* 4 References

## Genes

Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity.[10][11][12] Many candidate genes are highly expressed in the central nervous system.[13]

Several additional loci have been identified.[14] Also, several quantitative trait loci for BMI have been identified.

Confirmed and hypothesized associations include:

Condition  | OMIM  | Locus | Notes

|
|
|

leptin deficiency  | Online Mendelian Inheritance in Man (OMIM) 164160 | 7q31.3  |
leptin receptor deficiency  | Online Mendelian Inheritance in Man (OMIM) 601007 | 1p31  |
Ghrelin | 605353 | 3p25.3  |
Ghrelin receptor | 601898 | 3q26.31  |
prohormone convertase-1 deficiency  | Online Mendelian Inheritance in Man (OMIM) 600955 | 5q15-q21  |
proopiomelanocortin deficiency  | Online Mendelian Inheritance in Man (OMIM) 609734 | 2p23.3  |
melanocortin-4 receptor polymorphism (MC4R[15])  | Online Mendelian Inheritance in Man (OMIM) 155541 | 18q22  |
BMIQ1 |  | 7q32.3  | near D7S1804[16]
BMIQ2 |  | 13q14  | near D13S257[16]
BMIQ3 |  | 6q23-q25  | near D6S1009, GATA184A08, D6S2436, and D6S305[17]
BMIQ4 |  | 11q24  | near D11S1998, D11S4464, and D11S912[17]
BMIQ5 |  | 16p13
BMIQ6 |  | 20pter-p11.2  | near D20S482[18]
INSIG2[15] |  | 2q14.1  |
FTO[15] |  | 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.[19] This association disappeared, though, when those with FTO polymorphisms participated in moderately intensive physical activity equivalent to three to four hours of brisk walking.[20]
TMEM18[15] |  | 2p25.3  |
GNPDA2[15] |  | 4p13  |
NEGR1[15] |  | 1p31.1  |
BDNF[15] |  | 11p13  |
KCTD15[15] |  | 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.[21]
KLF14[22] |  | ?  | 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[23] |  | 16p11.2  |
MTCH2[23] |  | 11p11.2  |
PCSK1[23] |  | 5q15-q21  |
NPC1[24] |  | 18q11-q12  |
LYPLAL1[25] | 616548 | 1q41  | Disputed metabolic function of being either a lipase[26] or a short-chain carboxylesterase.[27]
CB1[28] | 114610 | 6q15  |
NPY5R[29] | 602001 | 4q32.2  |

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.[30]

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.[31] 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.[32]

Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.[33][34]

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.[35]

### 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.[36][37] Other candidate anti-obesity-related genes include ALK,[38] TBC1D1,[39] and SRA1.[40]

## Genetic syndromes

The term "non-syndromic obesity" is sometimes used to exclude these conditions.[41] 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.[42]

## See also

* New World Syndrome
* Nutritional genomics

Related:

* Human genetic variation

## References

1. ↑ 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. http://www.esst.org/newsletter2000.htm.
2. ↑ "Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective". Mol. Genet. Genomics 290 (4): 1191–221. Mar 2015. doi:10.1007/s00438-015-1015-9. PMID 25749980.
3. ↑ 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.
4. ↑ Kushner, Robert (2007). Treatment of the Obese Patient (Contemporary Endocrinology). Totowa, NJ: Humana Press. p. 158. ISBN 978-1-59745-400-1. https://books.google.com/books?id=vWjK5etS7PMC. Retrieved April 5, 2009.
5. ↑ "Obesity in anaesthesia and intensive care". Br J Anaesth 85 (1): 91–108. July 2000. doi:10.1093/bja/85.1.91. PMID 10927998.
6. ↑ "Genetic epidemiology of obesity". Epidemiol Rev 29: 49–61. 2007. doi:10.1093/epirev/mxm004. PMID 17566051.
7. ↑ Lyon, Helen N; Hirschhorn, Joel N (2005-07-01). "Genetics of common forms of obesity: a brief overview" (in en). The American Journal of Clinical Nutrition 82 (1): 215S–217S. doi:10.1093/ajcn/82.1.215S. ISSN 0002-9165. https://academic.oup.com/ajcn/article/82/1/215S/4863389.
8. ↑ "Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss". Arterioscler. Thromb. Vasc. Biol. 26 (5): 968–76. May 2006. doi:10.1161/01.ATV.0000216787.85457.f3. PMID 16627822.
9. ↑ 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.
10. ↑ Lee YS (January 2009). "The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature". Ann. Acad. Med. Singap. 38 (1): 34–44. doi:10.47102/annals-acadmedsg.V38N1p34. PMID 19221669. http://www.annals.edu.sg/pdf/38VolNo1Jan2009/V38N1p34.pdf. Retrieved 2009-06-08.
11. ↑ "Researchers discover DNA variants significantly influence body fat distribution" (in en-us). https://medicalxpress.com/news/2019-02-dna-variants-significantly-body-fat.html.
12. ↑ Lindgren, Cecilia M.; North, Kari E.; Loos, Ruth J. F.; Cupples, L. Adrienne; Hirschhorn, Joel N.; Kutalik, Zoltán; Rotter, Jerome I.; Mohlke, Karen L. et al. (18 February 2019). "Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution" (in en). Nature Genetics 51 (3): 452–469. doi:10.1038/s41588-018-0334-2. ISSN 1546-1718. PMID 30778226.
13. ↑ "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation". Nat. Genet. 41 (1): 25–34. January 2009. doi:10.1038/ng.287. PMID 19079261.
14. ↑ "OMIM - OBESITY". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601665.
15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 15.7 "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. May 2009. doi:10.1038/oby.2009.159. PMID 19478790.
16. ↑ 16.0 16.1 "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. January 2002. doi:10.1086/338144. PMID 11713718.
17. ↑ 17.0 17.1 "Genomewide Linkage Analysis of Body Mass Index across 28 Years of the Framingham Heart Study". Am. J. Hum. Genet. 71 (5): 1044–50. November 2002. doi:10.1086/343822. PMID 12355400.
18. ↑ Cite error: Invalid `<ref>` tag; no text was provided for refs named `pmid12774034`
19. ↑ "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. 2007. doi:10.1126/science.1141634. PMID 17434869.
20. ↑ "Physical activity and the association of common FTO gene variants with body mass index and obesity". Arch Intern Med 168 (16): 1791–97. 2008. doi:10.1001/archinte.168.16.1791. PMID 18779467.
21. ↑ 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.
22. ↑ "Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes". Nat. Genet. 43 (6): 561–4. June 2011. doi:10.1038/ng.833. PMID 21572415.
23. ↑ 23.0 23.1 23.2 "Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden". Hum. Mol. Genet. 18 (8): 1489–96. April 2009. doi:10.1093/hmg/ddp041. PMID 19164386.
24. ↑ 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.
25. ↑ Heid, Iris M.; Jackson, Anne U.; Randall, Joshua C.; Winkler, Thomas W.; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M. Carola et al. (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. PMID 20935629.
26. ↑ 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.
27. ↑ 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. PMID 22052940.
28. ↑ Pertwee, R G (June 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview" (in en). International Journal of Obesity 30 (S1): S13–S18. doi:10.1038/sj.ijo.0803272. ISSN 0307-0565. https://www.nature.com/articles/0803272.
29. ↑ MacNeil, Douglas J.. "NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity Drugs" (in en). Current Topics in Medicinal Chemistry 7 (17): 1721–1733. doi:10.2174/156802607782341028. https://www.eurekaselect.com/article/23898.
30. ↑ Kolata, Gina (2007). Rethinking thin: The new science of weight loss - and the myths and realities of dieting. Picador. pp. 122. ISBN 978-0-312-42785-6.
31. ↑ "Eating, exercise, and "thrifty" genotypes: Connecting the dots toward an evolutionary understanding of modern chronic diseases". J. Appl. Physiol. 96 (1): 3–10. 2004. doi:10.1152/japplphysiol.00757.2003. PMID 14660491.
32. ↑ 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.
33. ↑ Garland Jr, Theodore; Schutz, Heidi; Chappell, Mark A.; Keeney, Brooke K.; Meek, Thomas H.; Copes, Lynn E.; Acosta, Wendy; Drenowatz, Clemens et al. (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. PMID 21177942.
34. ↑ "Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice". Cell Metab 17 (1): 141–52. 2013. doi:10.1016/j.cmet.2012.12.007. PMID 23312289.
35. ↑ 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.
36. ↑ "Gene variants related to controlling body weight isolated" (in en). medicalxpress.com. https://medicalxpress.com/news/2021-07-gene-variants-body-weight-isolated.html.
37. ↑ Akbari, Parsa et al. (2 July 2021). "Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity" (in en). Science 373 (6550): eabf8683. doi:10.1126/science.abf8683. ISSN 0036-8075. PMID 34210852. PMC 10275396. https://www.science.org/doi/10.1126/science.abf8683.
38. ↑ Orthofer, Michael; Valsesia, Armand; Mägi, Reedik; Wang, Qiao-Ping; Kaczanowska, Joanna; Kozieradzki, Ivona; Leopoldi, Alexandra; Cikes, Domagoj et al. (11 June 2020). "Identification of ALK in Thinness" (in English). Cell 181 (6): 1246–1262.e22. doi:10.1016/j.cell.2020.04.034. ISSN 0092-8674. PMID 32442405.
39. ↑ Chadt, Alexandra; Leicht, Katja; Deshmukh, Atul; Jiang, Lake Q.; Scherneck, Stephan; Bernhardt, Ulrike; Dreja, Tanja; Vogel, Heike et al. (November 2008). "Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity" (in en). Nature Genetics 40 (11): 1354–1359. doi:10.1038/ng.244. ISSN 1546-1718. PMID 18931681.
40. ↑ 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. PMID 24675075.
41. ↑ "The genetic contribution to non-syndromic human obesity". Nat. Rev. Genet. 10 (7): 431–42. June 2009. doi:10.1038/nrg2594. PMID 19506576.
42. ↑ Farooqi, I. Sadaf; O’Rahilly, Stephen (2006). "Genetics of Obesity in Humans". Endocrine Reviews 27 (7): 710–718. doi:10.1210/er.2006-0040. PMID 17122358.

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