#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population


Autoři: Nathalie Chami aff001;  Michael Preuss aff001;  Ryan W. Walker aff003;  Arden Moscati aff001;  Ruth J. F. Loos aff001
Působiště autorů: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff001;  The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff002;  Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff003
Vyšlo v časopise: The role of polygenic susceptibility to obesity among carriers of pathogenic mutations in MC4R in the UK Biobank population. PLoS Med 17(7): e32767. doi:10.1371/journal.pmed.1003196
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003196

Souhrn

Background

Melanocortin 4 receptor (MC4R) deficiency, caused by mutations in MC4R, is the most common cause of monogenic forms of obesity. However, these mutations have often been identified in small-scale, case-focused studies. Here, we assess the penetrance of previously reported MC4R mutations at a population level. Furthermore, we examine why some carriers of pathogenic mutations remain of normal weight, to gain insight into the mechanisms that control body weight.

Methods and findings

We identified 59 known obesity-increasing mutations in MC4R from the Human Gene Mutation Database (HGMD) and Clinvar. We assessed their penetrance and effect on obesity (body mass index [BMI] ≥ 30 kg/m2) in >450,000 individuals (age 40–69 years) of the UK Biobank, a population-based cohort study. Of these 59 mutations, only 11 had moderate-to-high penetrance and increased the odds of obesity by more than 2-fold.

We subsequently focused on these 11 mutations and examined differences between carriers of normal weight and carriers with obesity. Twenty-eight of the 182 carriers of these 11 mutations were of normal weight. Body composition of carriers of normal weight was similar to noncarriers of normal weight, whereas among individuals with obesity, carriers had a somewhat higher BMI than noncarriers (1.44 ± 0.07 standard deviation scores [SDSs] ± standard error [SE] versus 1.29 ± 0.001, P = 0.03), because of greater lean mass (1.44 ± 0.09 versus 1.15 ± 0.002, P = 0.002). Carriers of normal weight more often reported that, already at age 10 years, their body size was below average or average (72%) compared with carriers with obesity (48%) (P = 0.01).

To assess the polygenic contribution to body weight in carriers of normal weight and carriers with obesity, we calculated a genome-wide polygenic risk score for BMI (PRSBMI). The PRSBMI of carriers of normal weight (PRSBMI = -0.64 ± 0.18) was significantly lower than of carriers with obesity (0.40 ± 0.11; P = 1.7 × 10−6), and tended to be lower than that of noncarriers of normal weight (−0.29 ± 0.003; P = 0.05). Among carriers, those with a low PRSBMI (bottom quartile) have an approximately 5-kg/m2 lower BMI (approximately 14 kg of body weight for a 1.7-m-tall person) than those with a high PRS (top quartile).

Because the UK Biobank population is healthier than the general population in the United Kingdom, penetrance may have been somewhat underestimated.

Conclusions

We showed that large-scale data are needed to validate the impact of mutations observed in small-scale and case-focused studies. Furthermore, we observed that despite the key role of MC4R in obesity, the effects of pathogenic MC4R mutations may be countered, at least in part, by a low polygenic risk potentially representing other innate mechanisms implicated in body weight regulation.

Klíčová slova:

Body Mass Index – Body weight – Genetic predisposition – Heredity – Mutation databases – Nonsense mutation – Obesity – Physical activity


Zdroje

1. Collaborators GBDO, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017; 377(1):13–27. doi: 10.1056/NEJMoa1614362 28604169

2. Collaboration NCDRF. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016;387(10026):1377–96. doi: 10.1016/S0140-6736(16)30054-X 27115820

3. Farooqi IS, O’Rahilly S. The Genetics of Obesity in Humans. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, et al., editors. Endotext. South Dartmouth (MA): 2000.

4. van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015;161(1):119–32. doi: 10.1016/j.cell.2015.03.008 25815990

5. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2000;106(2):271–9. doi: 10.1172/JCI9397 10903343

6. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–95. doi: 10.1056/NEJMoa022050 12646665

7. Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes. 2008;57(9):2511–8. doi: 10.2337/db08-0153 18559663

8. Martinelli CE, Keogh JM, Greenfield JR, Henning E, van der Klaauw AA, Blackwood A, et al. Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab. 2011;96(1):E181–8. doi: 10.1210/jc.2010-1369 21047921

9. Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2018;50(1):26–41. doi: 10.1038/s41588-017-0011-x 29273807

10. Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab. 1999;84(4):1483–6. doi: 10.1210/jcem.84.4.5728 10199800

11. Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ, et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet. 2018;55(9):578–86. doi: 10.1136/jmedgenet-2018-105315 29970488

12. Larsen LH, Echwald SM, Sorensen TI, Andersen T, Wulff BS, Pedersen O. Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. J Clin Endocrinol Metab. 2005;90(1):219–24. doi: 10.1210/jc.2004-0497 15486053

13. Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter AK, et al. Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. J Clin Endocrinol Metab. 2003;88(9):4258–67. doi: 10.1210/jc.2003-030233 12970296

14. Brumm H, Muhlhaus J, Bolze F, Scherag S, Hinney A, Hebebrand J, et al. Rescue of melanocortin 4 receptor (MC4R) nonsense mutations by aminoglycoside-mediated read-through. Obesity. 2012;20(5):1074–81. doi: 10.1038/oby.2011.202 21738238

15. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, Zhang S, et al. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab. 2006;91(5):1811–8. doi: 10.1210/jc.2005-1411 16507637

16. Calton MA, Ersoy BA, Zhang S, Kane JP, Malloy MJ, Pullinger CR, et al. Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study. Hum Mol Genet. 2009;18(6):1140–7. doi: 10.1093/hmg/ddn431 19091795

17. Xiang Z, Litherland SA, Sorensen NB, Proneth B, Wood MS, Shaw AM, et al. Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. Biochemistry. 2006;45(23):7277–88. doi: 10.1021/bi0600300 16752916

18. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203–9. doi: 10.1038/s41586-018-0579-z 30305743

19. Elliott P, Peakman TC, Biobank UK. The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. Int J Epidemiol. 2008;37(2):234–44. doi: 10.1093/ije/dym276 18381398

20. Collins R. What makes UK Biobank special? Lancet. 2012;379(9882):1173–4.

21. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779. doi: 10.1371/journal.pmed.1001779 25826379

22. UK Biobank. UK Biobank touchscreen questionnaire 2018 [Internet]. 2018 [cited 2020 May] https://www.ukbiobank.ac.uk/wp-content/uploads/2011/06/Touch_screen_questionnaire.pdf

23. VanItallie TB, Yang MU, Heymsfield SB, Funk RC, Boileau RA. Height-normalized indices of the body’s fat-free mass and fat mass: potentially useful indicators of nutritional status. Am J Clin Nutr. 1990;52(6):953–9. doi: 10.1093/ajcn/52.6.953 2239792

24. Townsend P. Deprivation. Journal of Social Policy. 1987;16:125–46.

25. Krawczak M, Ball EV, Fenton I, Stenson PD, Abeysinghe S, Thomas N, et al. Human gene mutation database-a biomedical information and research resource. Hum Mutat. 2000;15(1):45–51. doi: 10.1002/(SICI)1098-1004(200001)15:1<45::AID-HUMU10>3.0.CO;2-T 10612821

26. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–5. doi: 10.1093/nar/gkt1113 24234437

27. UK Biobank and Access Team UB. UK Biobank—Access Update—Reliability of genotype data for rare and very rare variants [Internet]. 2019 [cited NNNN].

28. Wright CF, West B, Tuke M, Jones SE, Patel K, Laver TW, et al. Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting. Am J Hum Genet. 2019;104(2):275–86. doi: 10.1016/j.ajhg.2018.12.015 30665703

29. Weedon MN, Jackson L, Harrison JW, Ruth KS, Tyrrell J, Hattersley AT, Wright CF. Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing. bioRxiv 696799 [Preprint]. 2019 [cited 2020 May]. https://doi.org/10.1101/696799

30. Euesden J, Lewis CM, O’Reilly PF. PRSice: Polygenic Risk Score software. Bioinformatics. 2015;31(9):1466–8. doi: 10.1093/bioinformatics/btu848 25550326

31. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197–206. doi: 10.1038/nature14177 25673413

32. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75. doi: 10.1086/519795 17701901

33. Lotta LA, Mokrosinski J, Mendes de Oliveira E, Li C, Sharp SJ, Luan J, et al. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell. 2019;177(3):597–607 e9. doi: 10.1016/j.cell.2019.03.044 31002796

34. Khera AV, Chaffin M, Wade KH, Zahid S, Brancale J, Xia R, et al. Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood. Cell. 2019;177(3):587–96 e9. doi: 10.1016/j.cell.2019.03.028 31002795

35. Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19(2):192–203. doi: 10.1038/gim.2016.90 27532257

36. Bick AG, Flannick J, Ito K, Cheng S, Vasan RS, Parfenov MG, et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet. 2012;91(3):513–9. doi: 10.1016/j.ajhg.2012.07.017 22958901

37. Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF, et al. Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med. 2016;8(322):322ra9. doi: 10.1126/scitranslmed.aad5169 26791950

38. Knoblauch H, Muller-Myhsok B, Busjahn A, Ben Avi L, Bahring S, Baron H, et al. A cholesterol-lowering gene maps to chromosome 13q. Am J Hum Genet. 2000;66(1):157–66. doi: 10.1086/302704 10631147

39. Oprea GE, Krober S, McWhorter ML, Rossoll W, Muller S, Krawczak M, et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science. 2008;320(5875):524–7. doi: 10.1126/science.1155085 18440926

40. Castel SE, Cervera A, Mohammadi P, Aguet F, Reverter F, Wolman A, et al. Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk. Nat Genet. 2018;50(9):1327–34. doi: 10.1038/s41588-018-0192-y 30127527

41. Chen R, Shi L, Hakenberg J, Naughton B, Sklar P, Zhang J, et al. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat Biotechnol. 2016;34(5):531–8. doi: 10.1038/nbt.3514 27065010

42. Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998;20(2):113–4. doi: 10.1038/2407 9771699

43. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20(2):111–2. doi: 10.1038/2404 9771698

44. Crowley JJ, Zhabotynsky V, Sun W, Huang S, Pakatci IK, Kim Y, et al. Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance. Nat Genet. 2015;47(4):353–60. doi: 10.1038/ng.3222 25730764

45. Matharu N, Rattanasopha S, Tamura S, Maliskova L, Wang Y, Bernard A, et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science. 2019;363(6424): eaau0629. doi: 10.1126/science.aau0629 30545847

46. Hatoum IJ, Stylopoulos N, Vanhoose AM, Boyd KL, Yin DP, Ellacott KL, et al. Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. J Clin Endocrinol Metab. 2012;97(6):E1023–31. doi: 10.1210/jc.2011-3432 22492873

47. Jelin EB, Daggag H, Speer AL, Hameed N, Lessan N, Barakat M, et al. Melanocortin-4 receptor signaling is not required for short-term weight loss after sleeve gastrectomy in pediatric patients. Int J Obes. 2016;40(3):550–3.

48. Censani M, Conroy R, Deng L, Oberfield SE, McMahon DJ, Zitsman JL, et al. Weight loss after bariatric surgery in morbidly obese adolescents with MC4R mutations. Obesity. 2014;22(1):225–31. doi: 10.1002/oby.20511 23740648

49. Hainerova I, Larsen LH, Holst B, Finkova M, Hainer V, Lebl J, et al. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. J Clin Endocrinol Metab. 2007;92(9):3689–96. doi: 10.1210/jc.2007-0352 17579204

50. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity. 2009;17(2):382–9. doi: 10.1038/oby.2008.422 18997677

51. Iepsen EW, Zhang J, Thomsen HS, Hansen EL, Hollensted M, Madsbad S, et al. Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist. Cell Metab. 2018(1);28:23–32 e3. doi: 10.1016/j.cmet.2018.05.008 29861388

52. Stafford M, Brunner EJ, Head J, Ross NA. Deprivation and the development of obesity a multilevel, longitudinal study in England. Am J Prev Med. 2010;39(2):130–9. doi: 10.1016/j.amepre.2010.03.021 20621260

53. Fry A, Littlejohns TJ, Sudlow C, Doherty N, Adamska L, Sprosen T, et al. Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population. Am J Epidemiol. 2017;186(9):1026–34. doi: 10.1093/aje/kwx246 28641372

54. Weng SF, Vaz L, Qureshi N, Kai J. Prediction of premature all-cause mortality: A prospective general population cohort study comparing machine-learning and standard epidemiological approaches. PLoS ONE. 2019;14(3):e0214365. doi: 10.1371/journal.pone.0214365 30917171

55. van Hout CV. Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank. biorxiv 572347 [Preprint]. 2019 [cited 2020 May]. https://doi.org/10.1101/572347


Článek vyšel v časopise

PLOS Medicine


2020 Číslo 7
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Halitóza
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#