Genome-Wide Association Study of Anorexia Nervosa (Price Foundation, Klarman Family Foundation, Center for Applied Genomics at the Children's Hospital of Philadelphia, Scripps Translational Sciences Institute Clinical Translational Science Award)

Twin studies are consistent with substantial heritability in anorexia nervosa (AN), although detecting and confirming individual risk alleles has been difficult, due to small effects of single alleles and limited samples in prior studies.

Methods: 1105 AN DNA samples obtained in a multisite study and 3733 pediatric patients of normal body weight were genotyped using the Illumina 610Q chip at The Center for Applied Genomics at The Children's Hospital of Philadelphia. Cases and controls were of European ancestry. Single nucleotide polymorphism (SNP) genotypes were subjected to quality control procedures, including elimination of SNPs with: call rates < 95%, minor allele frequency < 5%, and if Hardy-Weinberg equilibrium testing yielded p < 0.0001. Samples were removed if not of European ancestry or if showing cryptic relatedness. Eight AN DNA samples were deleted for low call rate, and 51 AN samples were deleted for cryptic relatedness. The statistical program, PLINK, was used to calculate a P value for each SNP passing quality control using the Cochran-Armitage trend test. The PennCNV program was used to define copy number variation (CNV).

Results: We performed a genome-wide association study (GWAS) using with 1033 AN cases and 3733 controls (genomic inflation factor = 1.08). There were 11 SNPs with P<1X10-5 [(rsID, chromosome location, nearest gene, distance to nearest gene (base-pair), P value) rs6959888, 7q21.13, ZNF804B, 0, 1.63E-06; rs17725255, 20p11.23, CSRP2BP, 39396, 1.72E-06; rs10494067, 1p13.3, NTNG1, 0, 5.83E-06; rs2383378, 14q12, AKAP6, 0, 6.41E-06; rs410644, 5q14.1, SSBP2, 40462, 6.74E-06; rs4479806, 5p14.1, CDH9, 156926, 7.79E-06; rs957788, 13q33.3, FAM155A, 0, 8.11E-06; rs830998, 2q31.1, LRP2, 0, 8.68E-06; rs6782029, 3p25.3, VGLL4, 0, 9.04E-06; rs512089, 9p21.3, ELAVL2, 47984, 9.85E-06; rs3808986, 11q24.3, APLP2, 29217, 9.92E-6]. CNV analyses were performed on 1015 AN cases and 3532 controls. Overall frequencies of common or rare CNVs were similar between cases and controls. Specific rare and large (>500 kb, <1%) CNVs of interest included deletion of a large (~1.4Mbp) region of chr13q12 found in 2 AN samples and at a 10 fold lower frequency in a large sample (72,918) of subjects containing the genes SGCG, SACS, TNFRSF19, MIPEP, PCOTH, C1QTNF9B, SPATA13, MIR2276, and C1QTNF9, and an overlapping deletion and a duplication observed in 3 AN samples overlapping the CNTN6 and CNTN4 genes. Partially overlapping ~ 30 kb duplications were seen in 12 AN cases and in 1 control at the CDC5L gene on chromosome 6. Partially overlapping deletion of the 3' half of the PSTPIP1 gene was seen in 5 AN cases and no controls. Finally, a ~ 60 kb deletion of the PLEC1 gene was observed in 5 AN cases and in none of 3532 controls.

Discussion: This is the first GWAS of AN. These preliminary results are consistent with absence of a major gene effect in AN. These results are consistent with genetic risk conveyed by multiple common alleles of small effect, as well as some uncommon CNVs of potentially larger effect. None of the implicated genes has a clear role in eating behavior. It must be emphasized that these results are preliminary and an additional ~ 400 AN cases will be analyzed as time and resources permit. These results require confirmation through study of independent populations of AN women.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1001
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH

Inclusion: Lifetime diagnosis of DSM-IV AN, with or without amenorrhea, at least 3 years before study entry and by age 45, body mass index at or below 18kg/m².

Exclusion: Lifetime diagnosis of DSM-IV BN, history of severe CNS trauma, psychotic disorder or developmental disability, or a medical or neurological condition such as type 1 diabetes that could confound the diagnosis of AN.

The DNA and clinical information for this dataset was initiated in 1992 and consists of a series of multi-center international collaborations involving investigators and institutes in the United States, Canada, England, Germany, and Italy. The studies have been supported by the Price Foundation and also involve a similar collaborative study supported by the NIMH.

• Primary Phenotype: Anorexia Nervosa
• Bulimia Nervosa

• Principal Investigator/Price Foundation Investigator
  • Walter Kaye, MD. Professor of Psychiatry, UCSD Eating Disorder Research and Treatment Program, UCSD Department of Psychiatry, San Diego, CA, USA.
• Co-Principal Investigators/Price Foundation Investigators
  • Wade Berrettini, MD. Director, Center of Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA, USA.
  • Andrew Bergen, PhD. Director, Molecular Genetics Program, Center for Health Sciences SRI International, Menlo Park, CA, USA.
  • Nicholas Schork, PhD. Director of Biostatistics and Bioinformatics, Scripps Translational Science Institute, Scripps Genomic Medicine, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
• Contributors/Price Foundation Investigators
  • Katherine Halmi, MD. Professor of Psychiatry, New York Presbyterian Hospital, Weill Medical College of Cornell University - Westchester Division, White Plains, NY, USA.
  • Manfred Fichter, MD. Professor of Psychiatry, Medizinisch-Psychosomatische Schon Klinik Roseneck, Prien, Germany.
  • Allan Kaplan, MD. Vice-Chair, Senior Scientist, Department of Psychiatry, Division of Behavioural Sciences and Health, Toronto General Research Institute, Toronto, ON, Canada.
  • Blake Woodside, MD. Affiliate Scientist, Department of Psychiatry, Division of Behavioural Sciences and Health, Toronto General Research Institute, Toronto, ON, Canada.
  • Michael Strober, MD. Stewart and Lynda Resnick Neuropsychiatric Hospital, Department of Psychiatry and Behavioral Science, UCLA, Los Angeles, CA, USA.
  • Janet Treasure, MD. Institute of Psychiatry King's College, Academic Psychiatry Guy's Hospital, London, Great Britain.
  • Alessandro Rotondro, MD. Department of Psychiatry, University of Pisa, Pisa, Italy.
  • James Mitchell, MD. President and Scientific Director, Neuropsychiatric Research Institute, Fargo, ND, USA.
  • Pamela Keel, PhD. Florida State University, Department of Psychology, Tallahassee, FL, USA.
  • Harry Brandt, MD. Director, Center for Eating Disorders at Sheppard Pratt, Department of Psychiatry, St. Joseph Medical Center, University of Maryland, Baltimore, MD, USA.
  • Steven Crawford, MD. Associate Director, Center For Eating Disorders at Sheppard Pratt, Towson, MD, USA.
  • Craig Johnson, PhD. Chief Clinical Officer, Eating Recovery Center, Denver, CO; University of Oklahoma College of Medicine, Oklahoma City, OK, USA.
  • Patrick Sullivan, MD, FRANZCP. Professor, Director, Psychiatric Genomics, University of North Carolina at Chapel Hill, Department of Psychiatric Genetics, Chapel Hill, NC, USA.
  • Scott Crow, MD. Professor of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
  • David Goldman, MD. Chief, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
  • Bernard Devlin, PhD. Associate Professor of Psychiatry, University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA.
  • Cynthia Bulik, PhD. William and Jeanne Jordan Distinguished Professor of Eating Disorders, Department of Psychiatry, University of North Carolina, Chapel Hill, NA, USA.
  • Kelly Klump, PhD. Professor of Psychology, Department of Psychiatry, Michigan State University, East Lansing, MI, USA.
  • Lisa Lilenfeld, PhD. Associate Professor, President, Eating Disorders Coalition for Research, Policy and Action, Clinical Psychology Program American School of Professional Psychology, Argosy University, Washington DC, USA.
  • Laura Thornton, PhD. Associate Research Professor, Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
  • Silviu Bacanu. Assistant Professor, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
  • Cinnamon Bloss. Assistant Professor, Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, La Jolla, CA, USA.
  • Ashley Van Zeeland, PhD. Director, Strategic Partnerships at Scripps Genomic Medicine Co-Founder at Cypher Genomics, Scripps Health and The Scripps Research Institute, La Jolla, CA, USA.
• Funding Source
  • Price Foundation Ltd. Geneva, Switzerland.