Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls

Molecular Genetics and Metabolism

Volumn 121, Issue 1, 2017, Pages 51-56

  Nordang, Gry B N ^a,b   Busk, Øyvind L ^b   Tveten, Kristian ^b   Hanevik, Hans Ivar ^c   Fell, Anne Kristin M ^b   Hjelmesæth, Jøran ^a,d   Holla, Øystein L ^b   Hertel, Jens K ^a  

^a VESTFOLD HOSPITAL TRUST   (Norway)

^b TELEMARK HOSPITAL   (Norway)

^c Telemark Hospital   (Norway)

^d UNIVERSITY OF OSLO   (Norway)

Author keywords

BMI; Morbid obesity; Mutation; Next generation sequencing; Rare sequence variant

Indexed keywords

GENOMIC DNA; HEMOGLOBIN A1C; HIGH DENSITY LIPOPROTEIN; LEPTIN; LEPTIN RECEPTOR; MELANOCORTIN 4 RECEPTOR; PROOPIOMELANOCORTIN; PROPROTEIN CONVERTASE 1; TRIACYLGLYCEROL; LEPTIN RECEPTOR, HUMAN; MC4R PROTEIN, HUMAN; PCSK1 PROTEIN, HUMAN;

ADOLESCENT; ADULT; ARTICLE; ASTHMA; BLOOD SAMPLING; BODY MASS; BODY WEIGHT; CHILD; CLINICAL FEATURE; COHORT ANALYSIS; COMORBIDITY; CONTROLLED STUDY; EXON; FAMILY HISTORY; FEMALE; GENE FREQUENCY; HETEROZYGOTE; HUMAN; HYPERTENSION; ISCHEMIC HEART DISEASE; MAJOR CLINICAL STUDY; MALE; METABOLIC SYNDROME X; MONOGENIC DISORDER; MORBID OBESITY; MUTATION RATE; NEXT GENERATION SEQUENCING; NON INSULIN DEPENDENT DIABETES MELLITUS; NORWEGIAN (PEOPLE); PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; RISK FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTOLIC BLOOD PRESSURE; WAIST CIRCUMFERENCE; AGE DISTRIBUTION; CASE CONTROL STUDY; DNA SEQUENCE; GENETIC PREDISPOSITION; GENETIC VARIATION; GENETICS; HIGH THROUGHPUT SEQUENCING; MIDDLE AGED; NORWAY; PROCEDURES; YOUNG ADULT;

ADOLESCENT; ADULT; AGE DISTRIBUTION; CASE-CONTROL STUDIES; CHILD; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; LEPTIN; MALE; MIDDLE AGED; MUTATION RATE; NORWAY; OBESITY, MORBID; PRO-OPIOMELANOCORTIN; PROPROTEIN CONVERTASE 1; RECEPTOR, MELANOCORTIN, TYPE 4; RECEPTORS, LEPTIN; SEQUENCE ANALYSIS, DNA; YOUNG ADULT;

EID: 85016400385     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2017.03.007     Document Type: Article

References (58)

1. [1] N.C.D.R.F. Collaboration. 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 387 (2016), 1377–1396.
2. [2] Stunkard, A.J., Harris, J.R., Pedersen, N.L., et al. The body-mass index of twins who have been reared apart. N. Engl. J. Med. 322 (1990), 1483–1487.
3. [3] Locke, A.E., Kahali, B., Berndt, S.I., et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518 (2015), 197–206.
4. [4] Manolio, T.A., Collins, F.S., Cox, N.J., et al. Finding the missing heritability of complex diseases. Nature 461 (2009), 747–753.
5. [5] Blakemore, A.I., Meyre, D., Delplanque, J., et al. A rare variant in the visfatin gene (NAMPT/PBEF1) is associated with protection from obesity. Obesity 17 (2009), 1549–1553.
6. [6] Meyre, D., Proulx, K., Kawagoe-Takaki, H., et al. Prevalence of loss-of-function FTO mutations in lean and obese individuals. Diabetes 59 (2010), 311–318.
7. [7] Sallman Almen, M., Rask-Andersen, M., Jacobsson, J.A., et al. Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children. Int. J. Obes. 37 (2013), 424–431.
8. [8] Gerhard, G.S., Chu, X., Wood, G.C., et al. Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity. Hum. Hered. 75 (2013), 144–151.
9. [9] Majithia, A.R., Flannick, J., Shahinian, P., et al. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 13127–13132.
10. [10] Paz-Filho, G., Mastronardi, C., Delibasi, T., et al. Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy. Arq. Bras. Endocrinol. Metabol. 54 (2010), 690–697.
11. [11] Clement, K., Vaisse, C., Lahlou, N., et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392 (1998), 398–401.
12. [12] Farooqi, I.S., Wangensteen, T., Collins, S., et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N. Engl. J. Med. 356 (2007), 237–247.
13. [13] Farooqi, I.S., Keogh, J.M., Yeo, G.S., et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348 (2003), 1085–1095.
14. [14] Vaisse, C., Clement, K., Guy-Grand, B., et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20 (1998), 113–114.
15. [15] Hinney, A., Schmidt, A., Nottebom, K., 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. 84 (1999), 1483–1486.
16. [16] Jackson, R.S., Creemers, J.W., Ohagi, S., et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16 (1997), 303–306.
17. [17] Philippe, J., Stijnen, P., Meyre, D., et al. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int. J. Obes. 39 (2015), 295–302.
18. [18] Krude, H., Biebermann, H., Luck, W., et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19 (1998), 155–157.
19. [19] Miraglia del Giudice, E., Cirillo, G., Santoro, N., et al. Molecular screening of the proopiomelanocortin (POMC) gene in Italian obese children: report of three new mutations. Int. J. Obes. Relat. Metab. Disord. 25 (2001), 61–67.
20. [20] Ramachandrappa, S., Farooqi, I.S., Genetic approaches to understanding human obesity. J. Clin. Invest. 121 (2011), 2080–2086.
21. [21] Graff, M., Ngwa, J.S., Workalemahu, T., et al. Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. Hum. Mol. Genet. 22 (2013), 3597–3607.
22. [22] Benzinou, M., Creemers, J.W., Choquet, H., et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat. Genet. 40 (2008), 943–945.
23. [23] Boycott, K.M., Vanstone, M.R., Bulman, D.E., et al. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14 (2013), 681–691.
24. [24] Richards, S., Aziz, N., Bale, S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17 (2015), 405–424.
25. [25] Jakobsen, G.S., Hofso, D., Roislien, J., et al. Morbidly obese patients–who undergoes bariatric surgery?. Obes. Surg. 20 (2010), 1142–1148.
26. [26] Valderhaug, T.G., Hertel, J.K., Nordstrand, N., et al. The association between hyperandrogenemia and the metabolic syndrome in morbidly obese women. Diabetol. Metab. Syndr., 7, 2015, 46.
27. [27] Abrahamsen, R., Svendsen, M.V., Henneberger, P.K., et al. Non-response in a cross-sectional study of respiratory health in Norway. BMJ Open, 6, 2016, e009912.
28. [28] Li, H., Durbin, R., Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 (2009), 1754–1760.
29. [29] McKenna, A., Hanna, M., Banks, E., et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20 (2010), 1297–1303.
30. [30] DePristo, M.A., Banks, E., Poplin, R., et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43 (2011), 491–498.
31. [31] Van der Auwera, G.A., Carneiro, M.O., Hartl, C., et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 11 (2013), 11 10 11–11 10 33.
32. [32] Wang, K., Li, M., Hakonarson, H., ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res., 38, 2010, e164.
33. [33] Vigeland, M.D., Gjotterud, K.S., Selmer, K.K., FILTUS: a desktop GUI for fast and efficient detection of disease-causing variants, including a novel autozygosity detector. Bioinformatics 32 (2016), 1592–1594.
34. [34] Alberti, K.G., Eckel, R.H., Grundy, S.M., et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120 (2009), 1640–1645.
35. [35] Shore, S.A., Obesity and asthma: implications for treatment. Curr. Opin. Pulm. Med. 13 (2007), 56–62.
36. [36] Gabrielsen, A.M., Lund, M.B., Kongerud, J., et al. The relationship between anthropometric measures, blood gases, and lung function in morbidly obese white subjects. Obes. Surg. 21 (2011), 485–491.
37. [37] Hallstrand, T.S., Fischer, M.E., Wurfel, M.M., et al. Genetic pleiotropy between asthma and obesity in a community-based sample of twins. J. Allergy Clin. Immunol. 116 (2005), 1235–1241.
38. [38] Thomsen, S.F., Ulrik, C.S., Kyvik, K.O., et al. Association between obesity and asthma in a twin cohort. Allergy 62 (2007), 1199–1204.
39. [39] Valderhaug, T.G., Aasheim, E.T., Sandbu, R., The association between severity of King's Obesity Staging Criteria scores and treatment choice in patients with morbid obesity: a retrospective cohort study. BMC Obes., 3, 2016.
40. [40] Ji, W., Foo, J.N., O'Roak, B.J., et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat. Genet. 40 (2008), 592–599.
41. [41] Kotowski, I.K., Pertsemlidis, A., Luke, A., et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78 (2006), 410–422.
42. [42] Melchior, C., Schulz, A., Windholz, J., et al. Clinical and functional relevance of melanocortin-4 receptor variants in obese German children. Horm. Res. Paediatr. 78 (2012), 237–246.
43. [43] Lubrano-Berthelier, C., Dubern, B., Lacorte, J.M., 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. 91 (2006), 1811–1818.
44. [44] Rouskas, K., Meyre, D., Stutzmann, F., et al. Loss-of-function mutations in MC4R are very rare in the Greek severely obese adult population. Obesity 20 (2012), 2278–2282.
45. [45] Vaisse, C., Clement, K., Durand, E., et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106 (2000), 253–262.
46. [46] Hinney, A., Bettecken, T., Tarnow, P., et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J. Clin. Endocrinol. Metab. 91 (2006), 1761–1769.
47. [47] Wangensteen, T., Kolsgaard, M.L., Mattingsdal, M., et al. Mutations in the melanocortin 4 receptor (MC4R) gene in obese patients in Norway. Exp. Clin. Endocrinol. Diabetes 117 (2009), 266–273.
48. [48] Huvenne, H., Le Beyec, J., Pepin, D., et al. Seven novel deleterious LEPR mutations found in early-onset obesity: a DeltaExon6-8 shared by subjects from Reunion Island, France, suggests a founder effect. J. Clin. Endocrinol. Metab. 100 (2015), E757–E766.
49. [49] Kimber, W., Peelman, F., Prieur, X., et al. Functional characterization of naturally occurring pathogenic mutations in the human leptin receptor. Endocrinology 149 (2008), 6043–6052.
50. [50] Farooqi, I.S., Keogh, J.M., Kamath, S., et al. Partial leptin deficiency and human adiposity. Nature 414 (2001), 34–35.
51. [51] Considine, R.V., Sinha, M.K., Heiman, M.L., et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334 (1996), 292–295.
52. [52] Kilpelainen, T.O., Carli, J.F., Skowronski, A.A., et al. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat. Commun., 7, 2016, 10494.
53. [53] Creemers, J.W., Choquet, H., Stijnen, P., et al. Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity. Diabetes 61 (2012), 383–390.
54. [54] Cawley, N.X., Li, Z., Loh, Y.P., 60 YEARS OF POMC: Biosynthesis, trafficking, and secretion of pro-opiomelanocortin-derived peptides. J. Mol. Endocrinol. 56 (2016), T77–T97.
55. [55] Challis, B.G., Pritchard, L.E., Creemers, J.W., et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum. Mol. Genet. 11 (2002), 1997–2004.
56. [56] Lee, Y.S., Challis, B.G., Thompson, D.A., et al. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab. 3 (2006), 135–140.
57. [57] Adzhubei, I.A., Schmidt, S., Peshkin, L., et al. A method and server for predicting damaging missense mutations. Nat. Methods 7 (2010), 248–249.
58. [58] Ioannidis, N.M., Rothstein, J.H., Pejaver, V., et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99 (2016), 877–885.