A genome-wide association study of anorexia nervosa.

Anorexia Nervosa/genetics; Asian Continental Ancestry Group/genetics; Calcineurin/genetics; Carrier Proteins/genetics; Case-Control Studies; Cullin Proteins/genetics; European Continental Ancestry Group/genetics; Female; Genome-Wide Association Study; Guanine Nucleotide Exchange Factors/genetics; Humans; Japan; Male; Meta-Analysis as Topic; Nuclear Proteins/genetics; Polymorphism, Single Nucleotide

Abstract :

[en] Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 x 10(-7)) in SOX2OT and rs17030795 (P=5.84 x 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 x 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 x 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 x 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Disciplines :

Genetics & genetic processes

Author, co-author :

Boraska, Vesna; Wellcome Trust Sanger Institute

Franklin, Christopher S.; Wellcome Trust Sanger Institute

Floyd, James A. B.; Wellcome Trust Sanger Institute

Thornton, Laura M.

Huckins, Laura M.

Southam, Lorraine

Rayner, Nigel William

Tachmazidou, Ioanna

Klump, Kelly L.

Treasure, Janet

More authors (166 more)

Language :

English

Title :

A genome-wide association study of anorexia nervosa.

Publication date :

2014

Journal title :

Molecular Psychiatry

ISSN :

1359-4184

eISSN :

1476-5578

Publisher :

Nature Publishing Group, United Kingdom

Volume :

Issue :

Pages :

1085-94

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 03 March 2016

Statistics

Number of views

242 (12 by ULiège)

Number of downloads

263 (8 by ULiège)

More statistics

Scopus citations^®

230

Scopus citations^®
without self-citations

143

OpenCitations

237

OpenAlex citations

310

Bibliography

Klump KL, Bulik CM, Kaye WH, Treasure J, Tyson E. Academy for Eating Disorders position paper: eating disorders are serious mental illnesses. Int J Eat Disord 2009; 42: 97-103.
Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007; 61: 348-358.
Hoek H, van Hoeken D. Review of the prevalence and incidence of eating disorders. Int J Eat Disord 2003; 34: 383-396.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision American Psychiatric Press: Washington, DC, USA, 2000.
Lucas AR, Beard CM, O'Fallon WM, Kurland LT. 50-year trends in the incidence of anorexia nervosa in Rochester, Minn.: a population-based study. Am J Psychiatry 1991; 148: 917-922.
Nicholls DE, Lynn R, Viner RM. Childhood eating disorders: British National Surveillance Study. Br J Psychiatry 2011; 198: 295-301.
Bueno B, Krug I, Bulik CM, Jiménez-Murcia S, Granero R, Thornton L et al. Late onset eating disorders in Spain: clinical characteristics and therapeutic implications. J Clin Psychol 2014, 70: 1-17.
Katzman D. Medical complications in adolescents with anorexia nervosa: a review of the literature. Int J Eat Disord 2005; 37: S52-S59.
Sharp C, Freeman C. The medical complications of anorexia nervosa. Br J Psychiatry 1993; 162: 452-462.
Kaye W, Bulik C, Thornton L, Barbarich BS, Masters K, Price Foundation Collaborative Group. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am J Psychiatry 2004; 161: 2215-2221.
Godart N, Flament M, Perdereau F, Jeammet P. Comorbidity between eating disorders and anxiety disorders: a review. Int J Eat Disord 2002; 32: 253-270.
Fernandez-Aranda F, Pinheiro AP, Tozzi F, Thornton LM, Fichter MM, Halmi KA et al. Symptom profile of major depressive disorder in women with eating disorders. Aust N Z J Psychiatry 2007; 41: 24-31.
Berkman ND, Lohr KN, Bulik CM. Outcomes of eating disorders: a systematic review of the literature. Int J Eat Disord 2007; 40: 293-309.
Mathers CD, Vos ET, Stevenson CE, Begg SJ. The Australian Burden of Disease Study: measuring the loss of health from diseases, injuries and risk factors. Med J Aust 2000; 172: 592-596.
Sullivan PF. Mortality in anorexia nervosa. Am J Psychiatry 1995; 152: 1073-1074.
Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry 2011; 68: 724-731.
Birmingham C, Su J, Hlynsky J, Goldner E, Gao M. The mortality rate from anorexia nervosa. Int J Eat Disord 2005; 38: 143-146.
Millar HR, Wardell F, Vyvyan JP, Naji SA, Prescott GJ, Eagles JM. Anorexia nervosa mortality in Northeast Scotland, 1965-1999. Am J Psychiatry 2005; 162: 753-757.
Zipfel S, Lowe B, Reas DL, Deter HC, Herzog W. Long-term prognosis in anorexia nervosa: lessons from a 21-year follow-up study. Lancet 2000; 355: 721-722.
Bulik CM, Berkman ND, Brownley KA, Sedway JA, Lohr KN. Anorexia nervosa treatment: a systematic review of randomized controlled trials. Int J Eat Disord 2007; 40: 310-320.
Eating Disorders: Core Interventions in the Treatment and Management of Anorexia Nervosa, Bulimia Nervosa and Related Eating Disorders. http://www.nice.org.uk/page.aspx?o=1012392004, Accessed 15 November 2013.
McKenzie JM, Joyce PR. Hospitalization for anorexia nervosa. Int J Eat Disord 1992; 11: 235-241.
Krauth C, Buser K, Vogel H. How high are the costs of eating disorders - anorexia nervosa and bulimia nervosa - for German society? Eur J Health Econ 2002; 3: 244-250.
Striegel-Moore RH, Bulik CM. Risk factors for eating disorders. Am Psychol 2007; 62: 181-198.
Kas M, Kaye W, Mathes W, Bulik C. Interspecies genetics of eating disorders traits. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 318-327.
Strober M, Freeman R, Lampert C, Diamond J, Kaye W. Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am J Psychiatry 2000; 157: 393-401.
Lilenfeld L, Kaye W, Greeno C, Merikangas K, Plotnikov K, Pollice C et al. A controlled family study of restricting anorexia and bulimia nervosa: comorbidity in probands and disorders in first-degree relatives. Arch Gen Psychiatry 1998; 55: 603-610.
Bulik C, Sullivan P, Tozzi F, Furberg H, Lichtenstein P, Pedersen N. Prevalence, heritability and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 2006; 63: 305-312.
Klump KL, Miller KB, Keel PK, McGue M, Iacono WG. Genetic and environmental influences on anorexia nervosa syndromes in a population-based twin sample. Psychol Med 2001; 31: 737-740.
Wade TD, Bulik CM, Neale M, Kendler KS. Anorexia nervosa and major depression: shared genetic and environmental risk factors. Am J Psychiatry 2000; 157: 469-471.
Kortegaard LS, Hoerder K, Joergensen J, Gillberg C, Kyvik KO. A preliminary population-based twin study of self-reported eating disorder. Psychol Med 2001; 31: 361-365.
Bulik CM, Thornton LM, Root TL, Pisetsky EM, Lichtenstein P, Pedersen NL. Understanding the relation between anorexia nervosa and bulimia nervosa in a Swedish national twin sample. Biol Psychiatry 2010; 67: 71-77.
Grice DE, Halmi KA, Fichter MM, Strober M, Woodside DB, Treasure JT et al. Evidence for a susceptibility gene for anorexia nervosa on chromosome 1. Am J Hum Genet 2002; 70: 787-792.
Devlin B, Bacanu S, Klump K, Bulik C, Fichter M, Halmi K et al. Linkage analysis of anorexia nervosa incorporating behavioral covariates. Hum Mol Genet 2002; 11: 689-696.
Bacanu S, Bulik C, Klump K, Fichter M, Halmi K, Keel P. Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates. Am J Med Genet B Neuropsychiatr Genet 2005; 139: 61-68.
Slof-Op 't Landt M, van Furth E, Meulenbelt I, Slagboom P, Bartels M, Boomsma D et al. Eating disorders: From twin studies to candidate genes and beyond. Twin Res Hum Genet 2005; 16: 467-482.
Bulik CM, Slof-Op't Landt MC, van Furth EF, Sullivan PF. The genetics of anorexia nervosa. Ann Rev Nutr 2007; 27: 263-275.
Hinney A, Scherag S, Hebebrand J. Genetic findings in anorexia and bulimia nervosa. Prog Mol Biol Transl Sci 2010; 94: 241-270.
Hebebrand J, Remschmidt H. Anorexia nervosa viewed as an extreme weight condition: genetic implications. Hum Genet 1995; 95: 1-11.
Muller TD, Greene BH, Bellodi L, Cavallini MC, Cellini E, Di Bella D et al. Fat mass and obesity-associated gene (FTO) in eating disorders: evidence for association of the rs9939609 obesity risk allele with bulimia nervosa and anorexia nervosa. Obes Facts 2012; 5: 408-419.
Nakabayashi K, Komaki G, Tajima A, Ando T, Ishikawa M, Nomoto J et al. Identification of novel candidate loci for anorexia nervosa at 1q41 and 11q22 in Japanese by a genome-wide association analysis with microsatellite markers. J Hum Genet 2009; 54: 531-537.
Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 2011; 16: 949-959.
Scott-Van Zeeland AA, Bloss CS, Tewhey R, Bansal V, Torkamani A, Libiger O et al. Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 2013.
Gendall K, Joyce P, Carter F, McIntosh V, Jordan J, Bulik C. The psychobiology and diagnostic significance of amenorrhea in patients with anorexia nervosa. Fertil Steril 2006; 85: 1531-1535.
Pinheiro A, Thornton L, Plotonicov K, Tozzi T, Klump K, Berrettini W et al. Patterns of menstrual disturbance in eating disorders. Int J Eat Disord 2007; 40: 424-434.
Tozzi F, Thornton L, Klump K, Bulik C, Fichter M, Halmi K et al. Symptom fluctuation in eating disorders: correlates of diagnostic crossover. Am J Psychiatry 2005; 162: 732-740.
Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 2009; 5: e1000529.
Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F et al. Integrating common and rare genetic variation in diverse human populations. Nature 2010; 467: 52-58.
Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet 2010; 11: 499-511.
Magi R, Morris AP. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 2010; 11: 288.
Morris JA, Randall JC, Maller JB, Barrett JC. Evoker: a visualization tool for genotype intensity data. Bioinformatics 2010; 26: 1786-1787.
Huckins L, Boraska V, Franklin C, Floyd J, Southam L, Genetic Consortium for Anorexia Nervosa et al. Using ancestry-informative markers to identify fine structure across 15 populations of European origin. Eur J Hum Genet (in press).
Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ et al. Price Foundation Collaborative Group A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 2011; 16: 949-959.
Aulchenko YS, Ripke S, Isaacs A, van Duijn CM. GenABEL: an R library for genome-wide association analysis. Bioinformatics 2007; 23: 1294-1296.
Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet 2012; 44: 821-824.
Gauderman WJ. Candidate gene association analysis for a quantitative trait, using parent-offspring trios. Genet Epidemiol 2003; 25: 327-338.
R: A language and environment for statistical computing. http://www.R-project.org. 2008.
Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 2011; 88: 76-82.
Boraska V, Davis OS, Cherkas LF, Helder SG, Harris J, Krug I et al. Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 803-811.
Wade T, Gordon S, Medland S, Bulik CM, Heath A, Montgomery GW et al. Genetic variants associated with disordered eating. Int J Eat Disord 2013; 46: 594-608.
Fall T, Ingelsson E. Genome-wide association studies of obesity and metabolic syndrome. Mol Cell Endocrinol 2014; 382: 740-757.
Guo Y, Lanktree MB, Taylor KC, Hakonarson H, Lange LA, Keating BJ. Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. Hum Mol Genet 2013; 22: 184-201.
Neale BM, Medland SE, Ripke S, Asherson P, Franke B, Lesch KP et al. Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49: 884-897.
Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N et al. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43: 977-983.
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969-976.
Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G et al. A mega-analysis of genome-wide association studies for major depressive disorder. Molecular psychiatry 2013; 18: 497-511.
Watson HJ, Bulik CM. Update on the treatment of anorexia nervosa: review of clinical trials, practice guidelines and emerging interventions. Psychol Med 2012; 43: 2477-2500.
Gauderman WJ. Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 2002; 155: 478-484.
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937-948.
Hinney A, Hebebrand J. Three at one swoop! Obes Facts 2009; 2: 3-8.
Bradfield JP, Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM et al. A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 2012; 44: 526-531.
Scherag A, Dina C, Hinney A, Vatin V, Scherag S, Vogel CI et al. Two new loci for body-weight 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.
Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet 2012; 90: 7-24.
Sullivan PF, Daly MJ, O'Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet 2012; 13: 537-551.
Ripke S, O'Dushlaine C, Chambert K, Moran J, Kähler A, Akterin S et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013; 45: 1150-1159.