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Title: Genome-Wide Association Study of Anorexia Nervosa      
citations:
21079607
description:
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.
Identifier:
phs000679.v1.p1
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000679.v1.p1
authentication: simpleLogin
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authorization:
none
duaIndividual
name:
Anorexia Nervosa
Bulimia Nervosa
affiliations:
Professor of Psychiatry, UCSD Eating Disorder Research and Treatment Program, UCSD Department of Psychiatry, San Diego, CA, USA
name:
Walter Kaye, MD
roles:
Principal Investigator/Price Foundation Investigator
affiliations:
Director, Center of Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA, USA
name:
Wade Berrettini, MD
roles:
Co-Principal Investigators/Price Foundation Investigators
affiliations:
Director, Molecular Genetics Program, Center for Health Sciences SRI International, Menlo Park, CA, USA
name:
Andrew Bergen, PhD
roles:
Co-Principal Investigators/Price Foundation Investigators
affiliations:
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
name:
Nicholas Schork, PhD
roles:
Co-Principal Investigators/Price Foundation Investigators
affiliations:
Professor of Psychiatry, New York Presbyterian Hospital, Weill Medical College of Cornell University - Westchester Division, White Plains, NY, USA
name:
Katherine Halmi, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Professor of Psychiatry, Medizinisch-Psychosomatische Schon Klinik Roseneck, Prien, Germany
name:
Manfred Fichter, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Vice-Chair, Senior Scientist, Department of Psychiatry, Division of Behavioural Sciences and Health, Toronto General Research Institute, Toronto, ON, Canada
name:
Allan Kaplan, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Affiliate Scientist, Department of Psychiatry, Division of Behavioural Sciences and Health, Toronto General Research Institute, Toronto, ON, Canada
name:
Blake Woodside, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Stewart and Lynda Resnick Neuropsychiatric Hospital, Department of Psychiatry and Behavioral Science, UCLA, Los Angeles, CA, USA
name:
Michael Strober, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Institute of Psychiatry King's College, Academic Psychiatry Guy's Hospital, London, Great Britain
name:
Janet Treasure, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Department of Psychiatry, University of Pisa, Pisa, Italy
name:
Alessandro Rotondro, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
President and Scientific Director, Neuropsychiatric Research Institute, Fargo, ND, USA
name:
James Mitchell, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Florida State University, Department of Psychology, Tallahassee, FL, USA
name:
Pamela Keel, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Director, Center for Eating Disorders at Sheppard Pratt, Department of Psychiatry, St. Joseph Medical Center, University of Maryland, Baltimore, MD, USA
name:
Harry Brandt, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Associate Director, Center For Eating Disorders at Sheppard Pratt, Towson, MD, USA
name:
Steven Crawford, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Chief Clinical Officer, Eating Recovery Center, Denver, CO; University of Oklahoma College of Medicine, Oklahoma City, OK, USA
name:
Craig Johnson, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Professor, Director, Psychiatric Genomics, University of North Carolina at Chapel Hill, Department of Psychiatric Genetics, Chapel Hill, NC, USA
name:
Patrick Sullivan, MD, FRANZCP
roles:
Contributors/Price Foundation Investigators
affiliations:
Professor of Psychiatry, University of Minnesota, Minneapolis, MN, USA
name:
Scott Crow, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Chief, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
name:
David Goldman, MD
roles:
Contributors/Price Foundation Investigators
affiliations:
Associate Professor of Psychiatry, University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA
name:
Bernard Devlin, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
William and Jeanne Jordan Distinguished Professor of Eating Disorders, Department of Psychiatry, University of North Carolina, Chapel Hill, NA, USA
name:
Cynthia Bulik, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Professor of Psychology, Department of Psychiatry, Michigan State University, East Lansing, MI, USA
name:
Kelly Klump, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Associate Professor, President, Eating Disorders Coalition for Research, Policy and Action, Clinical Psychology Program American School of Professional Psychology, Argosy University, Washington DC, USA
name:
Lisa Lilenfeld, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Associate Research Professor, Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
name:
Laura Thornton, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Assistant Professor, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA
name:
Silviu Bacanu
roles:
Contributors/Price Foundation Investigators
affiliations:
Assistant Professor, Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, La Jolla, CA, USA
name:
Cinnamon Bloss
roles:
Contributors/Price Foundation Investigators
affiliations:
Director, Strategic Partnerships at Scripps Genomic Medicine Co-Founder at Cypher Genomics, Scripps Health and The Scripps Research Institute, La Jolla, CA, USA
name:
Ashley Van Zeeland, PhD
roles:
Contributors/Price Foundation Investigators
affiliations:
Geneva, Switzerland
name:
Price Foundation Ltd
roles:
Funding Source
performedBy:
TitleNameInstitute Principal Investigator/Price Foundation InvestigatorWalter Kaye, MDProfessor of Psychiatry, UCSD Eating Disorder Research and Treatment Program, UCSD Department of Psychiatry, San Diego, CA, USA Co-Principal Investigators/Price Foundation InvestigatorsWade Berrettini, MDDirector, Center of Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA, USA Co-Principal Investigators/Price Foundation InvestigatorsAndrew Bergen, PhDDirector, Molecular Genetics Program, Center for Health Sciences SRI International, Menlo Park, CA, USA Co-Principal Investigators/Price Foundation InvestigatorsNicholas Schork, PhDDirector 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 InvestigatorsKatherine Halmi, MDProfessor of Psychiatry, New York Presbyterian Hospital, Weill Medical College of Cornell University - Westchester Division, White Plains, NY, USA
downloadURL: https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=DUC&view_pdf&stacc=phs000679.v1.p1
Identifier:
phs000679.v1.p1_policy
name:
Data Use Certificate
Identifier:
1
name:
General Research Use
schedulesActivity:
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.
alternateIdentifiers:
yes
selectionCriteria:

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.

types:
Case-Control
dateReleased:
11-05-2013
version:
phs000679.v1.p1
dateModified:
04-02-2014
abbreviation:
NIMH
name:
NIMH
ID:
0
name:
dbGaP