Do common variants separate between obese melanocortin-4 receptor gene mutation carriers and non-carriers? the impact of cryptic relatedness

Hormone Research in Paediatrics

Volumn 77, Issue 6, 2012, Pages 358-368

  Mhlhaus, Jessica ^a   Ptter, Carolin ^b   Brumm, Harald ^a   Grallert, Harald ^c   Illig, Thomas ^c   Scherag, Susann ^b   Reinehr, Thomas ^d   Pott, Wilfried ^e   Albayrak, Özgr ^b   Wang, Hai Jun ^f   Bau, Anne Madeleine ^a   Wiegand, Susanna ^a   Grters, Annette ^a   Krude, Heiko ^a   Hebebrand, Johannes ^b   Hinney, Anke ^b   Biebermann, Heike ^a   Scherag, André ^b  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b UNIVERSITY OF DUISBURG ESSEN   (Germany)

^c INSTITUTE OF EPIDEMIOLOGY   (Germany)

^d UNIVERSITY OF WITTEN HERDECKE   (Germany)

^e Red Cross Children's Hospital Siegen   (Germany)

^f PEKING UNIVERSITY HEALTH SCIENCE CENTER   (China)

Author keywords

Cryptic relatedness; Haplotypes; MC4R; Mutations; Obesity

Indexed keywords

MELANOCORTIN 4 RECEPTOR;

ADOLESCENT; ADULT; ARTICLE; CHILD; CONTROLLED STUDY; DISEASE ASSOCIATION; FEMALE; GENE FREQUENCY; GENETIC ASSOCIATION; GENETIC VARIABILITY; HAPLOTYPE; HUMAN; LOSS OF FUNCTION MUTATION; MAJOR CLINICAL STUDY; MALE; OBESITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; SCHOOL CHILD; SENSITIVITY ANALYSIS; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM;

ADOLESCENT; ADULT; BODY MASS INDEX; CHILD; EPISTASIS, GENETIC; FEMALE; GENETIC VARIATION; GENOME-WIDE ASSOCIATION STUDY; HETEROZYGOTE; HUMANS; MALE; MUTATION; OBESITY; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTOR, MELANOCORTIN, TYPE 4; YOUNG ADULT;

EID: 84864357623     PISSN: 16632818     EISSN: 16632826     Source Type: Journal    
DOI: 10.1159/000338999     Document Type: Article

References (61)

1. Hindorff L, Junkins H, Manolio T: NHGRI catalog of published genome-wide association studies. http://wwwgenomegov/gwastudies (2010).
2. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA: Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009; 106: 9362-9367.
3. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Magi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segre AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpelainen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proenca C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, Heijer MD, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grassler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jorgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, Konig IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaloy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimaki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, Mulic R, Ngwa JS, Nelis M, Neville MJ, Nyholt DR, O'Donnell CJ, O'Rahilly S, Ong KK, Oostra B, Pare G, Parker AN, Perola M, Pichler I, Pietilainen KH, Platou CG, Polasek O, Pouta A, Rafelt S, Raitakari O, Rayner NW, Ridderstrale M, Rief W, Ruokonen A, Robertson NR, Rzehak P, Salomaa V, Sanders AR, Sandhu MS, Sanna S, Saramies J, Savolainen MJ, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick DS, Smit JH, Soranzo N, Sovio U, Stephens J, Surakka I, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tonjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, Waite LL, Wallaschofski H, Walters GB, Widen E, Wiegand S, Wild SH, Willemsen G, Witte DR, Witteman JC, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby JP, Farooqi IS, Hebebrand J, Huikuri HV, James AL, Kahonen M, Levinson DF, Macciardi F, Nieminen MS, Ohlsson C, Palmer LJ, Ridker PM, Stumvoll M, Beckmann JS, Boeing H, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Gronberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, Mc-Carroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, M IM, Hirschhorn JN, Ingelsson E, Loos RJ: Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937-948.
4. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orru M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3:e115.
5. Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schafer H, Hebebrand J: Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2007; 2:e1361.
6. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889-894. (Pubitemid 46764279)
7. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K: Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 18-24.
8. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O'Rahilly S, Purmann C, Rees MG, Ridderstrale M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, Hirschhorn JN: Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25-34.
9. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M, Vogel CI, Wallace C, Waterworth DM, Weedon MN, Willer CJ, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL: Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008; 40: 768-775. (Pubitemid 351748863)
10. Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P, Balding D, Scott J, Kooner JS: Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 2008; 40: 716-718. (Pubitemid 351748872)
11. Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S, Durand E, Vatin V, Degraeve F, Proenca C, Gaget S, Korner A, Kovacs P, Kiess W, Tichet J, Marre M, Hartikainen AL, Horber F, Potoczna N, Hercberg S, Levy-Marchal C, Pattou F, Heude B, Tauber M, McCarthy MI, Blakemore AI, Montpetit A, Polychronakos C, Weill J, Coin LJ, Asher J, Elliott P, Jarvelin MR, Visvikis-Siest S, Balkau B, Sladek R, Balding D, Walley A, Dina C, Froguel P: Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in european populations. Nat Genet 2009; 41: 157-159.
12. Scherag A, Dina C, Hinney A, Vatin V, Scherag S, Vogel CI, Muller TD, Grallert H, Wichmann HE, Balkau B, Heude B, Jarvelin MR, Hartikainen AL, Levy-Marchal C, Weill J, Delplanque J, Korner A, Kiess W, Kovacs P, Rayner NW, Prokopenko I, McCarthy MI, Schafer H, Jarick I, Boeing H, Fisher E, Reinehr T, Heinrich J, Rzehak P, Berdel D, Borte M, Biebermann H, Krude H, Rosskopf D, Rimmbach C, Rief W, Fromme T, Klingenspor M, Schurmann A, Schulz N, Nothen MM, Muhleisen TW, Erbel R, Jockel KH, Moebus S, Boes T, Illig T, Froguel P, Hebebrand J, Meyre D: Two new loci for bodyweight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet 2010; 6:e1000916.
13. O'Rahilly S, Farooqi IS: Human obesity as a heritable disorder of the central control of energy balance. Int J Obes (Lond) 2008; 32(suppl 7):S55-S61.
14. Tao YX: The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 2010; 31: 506-543.
15. Scherag A, Jarick I, Grothe J, Biebermann H, Scherag S, Volckmar AL, Vogel CI, Greene B, Hebebrand J, Hinney A: Investigation of a genome-wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin-4 receptor gene locus. PLoS One 2010; 5:e13967.
16. Hughes D, Wallace A, Taylor J, Tassabehji M, McMahon R, Hill A, Nevin N, Graham C: Fluorescent multiplex microsatellites used to define haplotypes associated with 75 CFTR mutations from the UK on 437 CF chromosomes. Hum Mutat 1996; 8: 229-235. (Pubitemid 26328007)
17. Elce A, Boccia A, Cardillo G, Giordano S, Tomaiuolo R, Paolella G, Castaldo G: Three novel CFTR polymorphic repeats improve segregation analysis for cystic fibrosis. Clin Chem 2009; 55: 1372-1379.
18. Borras E, Pineda M, Blanco I, Jewett EM, Wang F, Teule A, Caldes T, Urioste M, Martinez-Bouzas C, Brunet J, Balmana J, Torres A, Ramon y Cajal T, Sanz J, Perez-Cabornero L, Castellvi-Bel S, Alonso A, Lanas A, Gonzalez S, Moreno V, Gruber SB, Rosenberg NA, Mukherjee B, Lazaro C, Capella G: MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. Cancer Res 2010; 70: 7379-7391.
19. Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, Gerber G, Sina M, Gorg T, Mayer H, Siegfried W, Fichter M, Remschmidt H, Hebebrand J: 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: 1483-1486. (Pubitemid 30644420)
20. Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter AK, Brokamp B, Goldschmidt H, Siegfried W, Remschmidt H, Schafer H, Gudermann T, Hebebrand J: 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: 4258-4267. (Pubitemid 37153729)
21. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, Lichtner P, Scherag A, Nguyen TT, Schlumberger P, Rief W, Vollmert C, Illig T, Wichmann HE, Schafer H, Platzer M, Biebermann H, Meitinger T, Hebebrand J: Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative populationbased sample and obese adults from Germany. J Clin Endocrinol Metab 2006; 91: 1761-1769.
22. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, Hinney A: Lifestyle intervention in obese children with variations in the melanocortin-4 receptor gene. Obesity (Silver Spring) 2009; 17: 382-389.
23. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K: DBSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29: 308-311. (Pubitemid 32054478)
24. The International HapMap Project: The International HapMap Project. Nature 2003; 426: 789-796.
25. Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-265. (Pubitemid 40202029)
26. Schedel M, Carr D, Klopp N, Woitsch B, Illig T, Stachel D, Schmid I, Fritzsch C, Weiland SK, von Mutius E, Kabesch M: A signal transducer and activator of transcription 6 haplotype influences the regulation of serum IgE levels. J Allergy Clin Immunol 2004; 114: 1100-1105. (Pubitemid 39469150)
27. Staubert C, Tarnow P, Brumm H, Pitra C, Gudermann T, Gruters A, Schoneberg T, Biebermann H, Rompler H: Evolutionary aspects in evaluating mutations in the melanocortin-4 receptor. Endocrinology 2007; 148: 4642-4648. (Pubitemid 47481513)
28. Schoneberg T, Yun J, Wenkert D, Wess J: Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a co-expressed receptor polypeptide. EMBO J 1996; 15: 1283-1291. (Pubitemid 26093464)
29. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, Zhang S, Bertrais S, Hercberg S, Basdevant A, Clement K, Vaisse C: Melanocortin-4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotypephenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab 2006; 91: 1811-1818.
30. Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, Balkau B, Potoczna N, Horber F, O'Rahilly S, Farooqi IS, Froguel P, Meyre D: Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 2008; 57: 2511-2518.
31. 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: 1085-1095. (Pubitemid 36337319)
32. 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: 219-224. (Pubitemid 40116661)
33. Hebebrand J, Geller F, Dempfle A, Heinzel-Gutenbrunner M, Raab M, Gerber G, Wermter AK, Horro FF, Blundell J, Schafer H, Remschmidt H, Herpertz S, Hinney A: Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations. Mol Psychiatry 2004; 9: 796-800. (Pubitemid 39107968)
34. Sina M, Hinney A, Ziegler A, Neupert T, Mayer H, Siegfried W, Blum WF, Remschmidt H, Hebebrand J: Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene. Am J Hum Genet 1999; 65: 1501-1507. (Pubitemid 30468662)
35. Dempfle A, Hinney A, Heinzel-Gutenbrunner M, Raab M, Geller F, Gudermann T, Schafer H, Hebebrand J: Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J Med Genet 2004; 41: 795-800. (Pubitemid 39389299)
36. Biebermann H, Krude H, Elsner A, Chubanov V, Gudermann T, Gruters A: Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization. Diabetes 2003; 52: 2984-2988. (Pubitemid 37466869)
37. Tarnow P, Rediger A, Brumm H, Ambrugger P, Rettenbacher E, Widhalm K, Hinney A, Kleinau G, Schaefer M, Hebebrand J, Krause G, Gruters A, Biebermann H: A heterozygous mutation in the third transmembrane domain causes a dominant-negative effect on signalling capability of the MC4R. Obes Facts 2008; 1: 155-162.
38. Herold C, Becker T: Genetic association analysis with FAMHAP: a major program update. Bioinformatics 2009; 25: 134-136.
39. Becker T, Cichon S, Jonson E, Knapp M: Multiple testing in the context of haplotype analysis revisited: application to case-control data. Ann Hum Genet 2005; 69: 747-756. (Pubitemid 41556327)
40. Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O, Tounian P, Levy-Marchal C, Buzzetti R, Pinelli L, Balkau B, Horber F, Bougneres P, Froguel P, Meyre D: Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet 2007; 16: 1837-1844. (Pubitemid 47244532)
41. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P: Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000; 106: 253-262. (Pubitemid 30483129)
42. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S: Dominant and recessive inheritance of morbid obesity associated with melanocortin-4 receptor deficiency. J Clin Invest 2000; 106: 271-279. (Pubitemid 30483131)
43. Xiang Z, Litherland SA, Sorensen NB, Proneth B, Wood MS, Shaw AM, Millard WJ, Haskell-Luevano C: 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: 7277-7288. (Pubitemid 43877414)
44. Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM, de Andrade M, Feenstra B, Feingold E, Hayes MG, Hill WG, Landi MT, Alonso A, Lettre G, Lin P, Ling H, Lowe W, Mathias RA, Melbye M, Pugh E, Cornelis MC, Weir BS, Goddard ME, Visscher PM: Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 2011; 43: 519-525.
45. Tao YX: Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 2005; 239: 1-14.
46. Ho G, MacKenzie RG: Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. J Biol Chem 1999; 274: 35816-35822. (Pubitemid 129512886)
47. Zhang F, Deng HW: Confounding from cryptic relatedness in haplotype-based association studies. Genetica 2010; 138: 945-950.
48. Tao YX, Segaloff DL: Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and non-obese or obese subjects. J Clin Endocrinol Metab 2005; 90: 5632-5638. (Pubitemid 41415469)
49. Gu W, Tu Z, Kleyn PW, Kissebah A, Duprat L, Lee J, Chin W, Maruti S, Deng N, Fisher SL, Franco LS, Burn P, Yagaloff KA, Nathan J, Heymsfield S, Albu J, Pi-Sunyer FX, Allison DB: Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 1999; 48: 635-639. (Pubitemid 29106881)
50. Valli-Jaakola K, Lipsanen-Nyman M, Oksanen L, Hollenberg AN, Kontula K, Bjorbaek C, Schalin-Jantti C: Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults. J Clin Endocrinol Metab 2004; 89: 940-945. (Pubitemid 38269915)
51. Nijenhuis WA, Garner KM, van Rozen RJ, Adan RA: Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. J Biol Chem 2003; 278: 22939-22945. (Pubitemid 36830358)
52. Calton MA, Ersoy BA, Zhang S, Kane JP, Malloy MJ, Pullinger CR, Bromberg Y, Pennacchio LA, Dent R, McPherson R, Ahituv N, Vaisse C: 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: 1140-1147.
53. Kim DH, Shin SW, Baik JH: Role of third intracellular loop of the melanocortin-4 receptor in the regulation of constitutive activity. Biochem Biophys Res Commun 2008; 365: 439-445. (Pubitemid 350181676)
54. Fan ZC, Tao YX: Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. J Cell Mol Med 2009; 13: 3268-3282.
55. Hughes DA, Hinney A, Brumm H, Wermter AK, Biebermann H, Hebebrand J, Stoneking M: Increased constraints on MC4R during primate and human evolution. Hum Genet 2009; 124: 633-647.
56. Tao YX, Segaloff DL: Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 2003; 144: 4544-4551. (Pubitemid 37204854)
57. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P, Vaisse C: Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003; 12: 145-153. (Pubitemid 36124450)
58. Van Leeuwen D, Steffey ME, Donahue C, Ho G, MacKenzie RG: Cell surface expression of the melanocortin-4 receptor is dependent on a C-terminal di-isoleucine sequence at codons 316/317. J Biol Chem 2003; 278: 15935-15940. (Pubitemid 36799711)
59. Xiang Z, Proneth B, Dirain ML, Litherland SA, Haskell-Luevano C: Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist. Biochemistry 2010; 49: 4583-4600.
60. Santini F, Maffei M, Ceccarini G, Pelosini C, Scartabelli G, Rosellini V, Chiellini C, Marsili A, Lisi S, Tonacchera M, Agretti P, Chiovato L, Mammoli C, Vitti P, Pinchera A: Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation. J Clin Endocrinol Metab 2004; 89: 904-908. (Pubitemid 38269909)
61. Brumm H, Muhlhaus J, Bolze F, Scherag S, Hinney A, Hebebrand J, Wiegand S, Klingenspor M, Gruters A, Krude H, Biebermann H: Rescue of melanocortin-4 receptor ( MC4R ) nonsense mutations by aminoglycoside-mediated read-through. Obesity (Silver Spring) 2012; 20: 1074-1081.