Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees
Publication: American Journal of Psychiatry
Abstract
Objective
The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).
Method
The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs.
Results
No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10−17, explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families.
Conclusions
Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.
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History
Received: 23 September 2011
Revision received: 17 April 2012
Accepted: 7 May 2012
Published online: 1 September 2012
Published in print: September 2012
Authors
Funding Information
Dr. O’Donovan’s institution received an honorarium from Lilly with respect to a presentation he gave at a satellite meeting of the Japanese Schizophrenia Society. Dr. Hansen works for Illumina, Inc. Dr. Mallet is founder and part owner of Newvectys, Inc. (Paris). Dr. Maier has received research grants from, is a member of the advisory boards of, or receives speaking fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Merck, Pfizer, Sanofi-Aventis, Schering, and Böhringer. Dr. Papadimitriou has been on speakers or advisory boards for or has received travel expenses, honoraria, or consultancy fees for participation in research and in clinical expert groups from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Pfizer, Sanofi, Servier, and Wyeth; he has also received unrestricted grants from AstraZeneca, Janssen, and Lilly for the Department of Psychiatry of Eginition Hospital (Athens University), of which he is the chairman. Dr. Dikeos has been on speakers or advisory boards for or has received honoraria or travel expenses from AstraZeneca, Boehringer, Bristol, Eli Lilly, Genesis Pharma, GlaxoSmithKline, Janssen, Lundbeck, Sanofi, UniPharma, and Wyeth; he has also received consultancy fees for participation in research for Eli Lilly and for participation in clinical expert groups for Bristol Myers Squibb and unrestricted grants from Lilly and AstraZeneca for the Sleep Research Unit of Eginition Hospital (Athens University), of which he is director. Dr. Jay and Ms. Lasseter are deceased and had no competing interests during this study. The remaining authors report no financial relationships with commercial interests.
Supplementary Material
Supported by NIMH grant R01MH062276 (to Drs. Levinson, Laurent, Owen, and Wildenauer), grant R01MH068922 (to Dr. Gejman), grant R01MH068921 (to Dr. Pulver) and grant R01MH068881 (to Dr. Riley). Data from the Molecular Genetics of Schizophrenia data set are available from the NIMH Center for Genetic Studies (http://nimhgenetics.org) and dbGAP (http://www.ncbi.nlm.nih.gov/gap); they were collected under funding by collaborative NIMH grants to NorthShore University HealthSystem, Evanston, Ill. (MH59571; Pablo V. Gejman, M.D., collaboration coordinator and principal investigator; and Alan R. Sanders, M.D.); Stanford University, Palo Alto, Calif. (MH61675; Douglas F. Levinson, M.D., principal investigator); Louisiana State University, New Orleans (MH67257; Nancy G. Buccola, A.P.R.N., B.C., principal investigator); University of Queensland, Brisbane, Queensland, Australia (MH59588; Bryan J. Mowry, M.D., principal investigator); University of Colorado, Denver (MH59565; Robert Freedman, M.D., principal investigator; and Ann Olincy, M.D.); Emory University School of Medicine, Atlanta (MH59587; Farooq Amin, M.D., principal investigator); University of Iowa, Iowa City (MH59566; Donald W. Black, M.D., principal investigator; and Raymond R. Crowe, M.D.); Mount Sinai School of Medicine, New York (MH59586; Jeremy M. Silverman, Ph.D., principal investigator); University of California, San Francisco (MH60870; William F. Byerley, M.D., principal investigator); and Washington University, St. Louis (MH60879; C. Robert Cloninger, M.D., principal investigator).Metrics & Citations
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