Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa


Anorexia nervosa (AN) is a mental illness with high mortality that most commonly afflicts adolescent female individuals. Clinical symptoms include chronic food refusal, weight loss and body image distortions. We carried out a genome-wide association study on 1033 AN cases and 3733 pediatric control subjects, all of whom were of European ancestry and were genotyped on the Illumina HumanHap610 platform (Illumina, San Diego, CA, USA). We confirmed that common single-nucleotide polymorphisms (SNPs) within OPRD1 (rs533123, P=0.0015) confer risk for AN, and obtained suggestive evidence that common SNPs near HTR1D (rs7532266, P=0.04) confer risk for restricting-type AN specifically. However, no SNPs reached genome-wide significance in our data, whereas top association signals were detected near ZNF804B, CSRP2BP, NTNG1, AKAP6 and CDH9. In parallel, we performed genome-wide analysis on copy number variations (CNVs) using the signal intensity data from the SNP arrays. We did not find evidence that AN cases have more CNVs than control subjects, nor do they have over-representation of rare or large CNVs. However, we identified several regions with rare CNVs that were only observed in AN cases, including a recurrent 13q12 deletion (1.5 Mb) disrupting SCAS in two cases, and CNVs disrupting the CNTN6/CNTN4 region in several AN cases. In conclusion, our study suggests that both common SNPs and rare CNVs may confer genetic risk to AN. These results point to intriguing genes that await further validation in independent cohorts for confirmatory roles in AN.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2


  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Publishing, Inc, 2000.

  2. Hudson JI, Hiripi E, Pope Jr HG, Kessler RC . The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007; 61: 348–358.

    Article  Google Scholar 

  3. Attia E . Anorexia nervosa: current status and future directions. Annu Rev Med 2010; 61: 425–435.

    Article  CAS  Google Scholar 

  4. Papadopoulos FC, Ekbom A, Brandt L, Ekselius L . Excess mortality, causes of death and prognostic factors in anorexia nervosa. Br J Psychiatry 2009; 194: 10–17.

    Article  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. Lilenfeld LR, Kaye WH, Greeno CG, Merikangas KR, Plotnicov K, Pollice C et al. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity. Arch Gen Psychiatry 1998; 55: 603–610.

    Article  CAS  Google Scholar 

  7. Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL . Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 2006; 63: 305–312.

    Article  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Pinheiro AP, Root T, Bulik CM . The genetics of anorexia nervosa: current findings and future perspectives. Int J Child Adolesc Health 2009; 2: 153–164.

    PubMed  PubMed Central  Google Scholar 

  10. Bulik CM, Slof-Op’t Landt MC, van Furth EF, Sullivan PF . The genetics of anorexia nervosa. Annu Rev Nutr 2007; 27: 263–275.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Bergen AW, van den Bree MB, Yeager M, Welch R, Ganjei JK, Haque K et al. Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa. Mol Psychiatry 2003; 8: 397–406.

    Article  CAS  Google Scholar 

  13. Brown KM, Bujac SR, Mann ET, Campbell DA, Stubbins MJ, Blundell JE . Further evidence of association of OPRD1 & HTR1D polymorphisms with susceptibility to anorexia nervosa. Biol Psychiatry 2007; 61: 367–373.

    Article  CAS  Google Scholar 

  14. Devlin B, Bacanu SA, Klump KL, Bulik CM, Fichter MM, Halmi KA et al. Linkage analysis of anorexia nervosa incorporating behavioral covariates. Hum Mol Genet 2002; 11: 689–696.

    Article  CAS  Google Scholar 

  15. Bacanu SA, Bulik CM, Klump KL, Fichter MM, Halmi KA, Keel P et al. 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; 139B: 61–68.

    Article  CAS  Google Scholar 

  16. Gorwood P, Ades J, Bellodi L, Cellini E, Collier DA, Di Bella D et al. The 5-HT(2A) -1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres. Mol Psychiatry 2002; 7: 90–94.

    Article  CAS  Google Scholar 

  17. Bergen AW, Yeager M, Welch RA, Haque K, Ganjei JK, van den Bree MB et al. Association of multiple DRD2 polymorphisms with anorexia nervosa. Neuropsychopharmacology 2005; 30: 1703–1710.

    Article  CAS  Google Scholar 

  18. Gabrovsek M, Brecelj-Anderluh M, Bellodi L, Cellini E, Di Bella D, Estivill X et al. Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet 2004; 124B: 68–72.

    Article  CAS  Google Scholar 

  19. Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004; 13: 1205–1212.

    Article  CAS  Google Scholar 

  20. Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M et al. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Eur J Hum Genet 2005; 13: 428–434.

    Article  CAS  Google Scholar 

  21. Cellini E, Nacmias B, Brecelj-Anderluh M, Badia-Casanovas A, Bellodi L, Boni C et al. Case-control and combined family trios analysis of three polymorphisms in the ghrelin gene in European patients with anorexia and bulimia nervosa. Psychiatr Genet 2006; 16: 51–52.

    Article  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. Cook Jr EH, Scherer SW . Copy-number variations associated with neuropsychiatric conditions. Nature 2008; 455: 919–923.

    Article  CAS  Google Scholar 

  24. Kaye WH, Lilenfeld LR, Berrettini WH, Strober M, Devlin B, Klump KL et al. A search for susceptibility loci for anorexia nervosa: methods and sample description. Biol Psychiatry 2000; 47: 794–803.

    Article  CAS  Google Scholar 

  25. Gendall KA, Joyce PR, Carter FA, McIntosh VV, Jordan J, Bulik CM . The psychobiology and diagnostic significance of amenorrhea in patients with anorexia nervosa. Fertil Steril 2006; 85: 1531–1535.

    Article  Google Scholar 

  26. Hebebrand J, Himmelmann GW, Heseker H, Schafer H, Remschmidt H . Use of percentiles for the body mass index in anorexia nervosa: diagnostic, epidemiological, and therapeutic considerations. Int J Eat Disord 1996; 19: 359–369.

    Article  CAS  Google Scholar 

  27. Fichter MM, Herpertz S, Quadflieg N, Herpertz-Dahlmann B . Structured interview for anorexic and bulimic disorders for DSM-IV and ICD-10: updated (third) revision. Int J Eat Disord 1998; 24: 227–249.

    Article  CAS  Google Scholar 

  28. Garner D . Eating Disorders Inventory-2: Professional Manual. Psychological Assessment Resources, Inc.: Odessa, FL, 1991.

    Google Scholar 

  29. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al. The yale-brown obsessive compulsive scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46: 1006–1011.

    Article  CAS  Google Scholar 

  30. Cloninger CR, Przybeck TR, Svrakic DM, Wetzel RD . The Temperament and Character Inventory (TCI): A Guide to Its Development and Use. Center for Psychobiology of Personality, Washington University: St Louis, MO, 1994.

    Google Scholar 

  31. Frost R, Marten P, Lahart C, Rosenblate R . The dimensions of perfectionism. Cognit Ther Res 1990; 14: 449–468.

    Article  Google Scholar 

  32. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008; 9: 356–369.

    Article  CAS  Google Scholar 

  33. 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: 559–575.

    Article  CAS  Google Scholar 

  34. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SFA et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007; 17: 1665–1674.

    Article  CAS  Google Scholar 

  35. Diskin SJ, Li M, Hou C, Yang S, Glessner J, Hakonarson H et al. Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms. Nucleic Acids Res 2008; 36: e126.

    Article  Google Scholar 

  36. O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.

    Article  Google Scholar 

  37. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009; 459: 528–533.

    Article  CAS  Google Scholar 

  38. Koronyo-Hamaoui M, Gak E, Stein D, Frisch A, Danziger Y, Leor S et al. CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population. Am J Med Genet B Neuropsychiatr Genet 2004; 131B: 76–80.

    Article  Google Scholar 

  39. Koronyo-Hamaoui M, Danziger Y, Frisch A, Stein D, Leor S, Laufer N et al. Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study. Mol Psychiatry 2002; 7: 82–85.

    Article  CAS  Google Scholar 

  40. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241.

    Article  Google Scholar 

  41. Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL et al. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet 2009; 5: e1000373.

    Article  Google Scholar 

  42. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009; 459: 569–573.

    Article  CAS  Google Scholar 

  43. Zhang D, Cheng L, Qian Y, Alliey-Rodriguez N, Kelsoe JR, Greenwood T et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry 2009; 14: 376–380.

    Article  CAS  Google Scholar 

  44. Stefansson H, Rujescu D, Cichon S, Pietilainen O, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236.

    Article  CAS  Google Scholar 

  45. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667–675.

    Article  CAS  Google Scholar 

  46. Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 2009; 41: 160–162.

    Article  CAS  Google Scholar 

  47. Rujescu D, Ingason A, Cichon S, Pietilainen OP, Barnes MR, Toulopoulou T et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 2009; 18: 988–996.

    Article  CAS  Google Scholar 

  48. Ingason A, Rujescu D, Cichon S, Sigurdsson E, Sigmundsson T, Pietilainen OP et al. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry 2009.

  49. Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B et al. ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 2000; 24: 120–125.

    Article  CAS  Google Scholar 

  50. Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A et al. Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 2004; 74: 1286–1293.

    Article  CAS  Google Scholar 

  51. Roohi J, Montagna C, Tegay DH, Palmer LE, DeVincent C, Pomeroy JC et al. Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet 2009; 46: 176–182.

    Article  CAS  Google Scholar 

  52. Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y et al. Origins and functional impact of copy number variation in the human genome. Nature 2009; 464: 704–712.

    Article  Google Scholar 

Download references


We gratefully thank all the patients and their families who were enrolled in this study, as well as all the control subjects who donated blood samples to Children's Hospital of Philadelphia (CHOP) for genetic research purposes. We thank the Price Foundation for their support of the Collaborative Group effort that was responsible for recruitment of patients, collection of clinical information and provision of the DNA samples used in this study. The authors also thank the Klarman Family Foundation for supporting the study. We thank the technical staff at the Center for Applied Genomics at CHOP for producing the genotypes used for analyses and the nursing, medical assistant and medical staff for their invaluable help with sample recruitments. CTB and NJS are funded in part by the Scripps Translational Sciences Institute Clinical Translational Science Award [Grant Number U54 RR0252204-01]. All genome-wide genotyping was funded by an Institute Development Award to the Center for Applied Genomics from the CHOP.

Author information

Authors and Affiliations



Corresponding author

Correspondence to H Hakonarson.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

PowerPoint slides

Supplementary information



Members of the Price Foundation Collaborative Group

Harry Brandt7, Steve Crawford7, Scott Crow8, Manfred M Fichter9, Katherine A Halmi10, Craig Johnson11, Allan S Kaplan12,13,14, Maria La Via15, James Mitchell16,17, Michael Strober18, Alessandro Rotondo19, Janet Treasure20, D Blake Woodside13,14,21, Cynthia M Bulik15,22, Pamela Keel21, Kelly L Klump23, Lisa Lilenfeld24, Laura M Thornton15, Kathy Plotnicov25, Andrew W Bergen26 and Pierre Magistretti27

7Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

8Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA

9Roseneck Hospital for Behavioral Medicine, Prien, Germany and Department of Psychiatry, University of Munich (LMU), Munich, Germany

10New York Presbyterian Hospital-Westchester Division, Weill Medical College of Cornell, University, White Plains, NY, USA

11Eating Recovery Center, Denver, Colorado, USA

12Center for Addiction and Mental Health, Toronto, Canada

13Department of Psychiatry, Toronto General Hospital, University Health Network, Toronto, Canada

14Department of Psychiatry, University of Toronto, Toronto, Canada

15Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

16Neuropsychiatric Research Institute, Fargo, ND, USA

17Department of Clinical Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA

18Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

19Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, University of Pisa, Pisa, Italy

20Dept Academic Psychiatry, Bermondsey Wing Guys Hospital, University of London, UK

21Department of Psychology, Florida State University, Tallahassee, FL, USA

22Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

23Department of Psychology, Michigan State University, East Lansing, MI, USA

24Clinical Psychology Program, Argosy University, Washington, DC, USA

25Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

26Center for Health Sciences, SRI International, Menlo Park, CA, USA

27Brain Mind Institute, EPFLCH-1015 Lausanne, Switzerland

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, K., Zhang, H., Bloss, C. et al. A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 16, 949–959 (2011).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


This article is cited by


Quick links