Genome-wide association study of multiplex schizophrenia pedigrees


Douglas F. Levinson, Stanford University
Jiaxin Shi, Stanford University
Kai Wang, Stanford University
Sang Oh, Stanford University
Brien Riley, Virginia Commonwealth University
Ann E. Pulver, Johns Hopkins University School of Medicine
Dieter B. Wildenauer, University of Western Australia
Claudine Laurent, Universite Pierre et Marie Curie
Bryan J. Mowry, University of Queensland
Pablo V. Gejman, Northwestern University
Michael J. Owen, Cardiff University
Kenneth S. Kendler, Virginia Commonwealth University
Gerald Nestadt, Johns Hopkins University
Sibylle G. Schwab, University of Western AustraliaFollow
Jacques Mallet, Hpital de la Pitie
Deborah Nertney, University of Queensland
Alan R. Sanders, Northwestern University
Nigel Williams, Bournemouth University
Brandon Wormley, Virginia Commonwealth University
Virginia K. Lasseter, Johns Hopkins University
Margot Albus, Mental State Hospital
Stephanie Godard-Bauche, Hopital de la Pitie-Salpetriere
Madeline Alexander, Stanford University
Jubao Duan, Northwestern University
Michael C. O'Donovan, Cardiff University
Dermot Walsh, Health Research Board
Anthony O'Neill, Queens University
George N. Papadimitriou, University of Athens
Dimitris Dikeos, University of Athens
Wolfgang Maier, University of Bonn
Bernard Lerer, Stanford University
Dominique Campion, Stanford University
David Cohen, University of New South Wales
Maurice Jay, Universite Pierre et Marie Curie
Ayman Fanous, Stanford University
Peter Eichhammer, Stanford University
Jeremy M. Silverman, Mt. Sinai School of Medicine
Nadine Norton, Cardiff University
Nancy Zhang, Stanford University
Hakon Hakonarson, Stanford University
Cynthia Gao, Stanford University
Ami Citri, Stanford University
Mark Hansen, Stanford University
Stephan Ripke, Stanford University
Frank Dudbridge, Stanford University
Peter A. Holmans, Cardiff University



Publication Details

Levinson, D. F., Shi, J., Wang, K., Oh, S., Riley, B., Pulver, A. E., Wildenauer, D. B., Laurent, C., Mowry, B. J., Gejman, P. V., Owen, M. J., Kendler, K. S., Nestadt, G., Schwab, S. G., Mallet, J., Nertney, D., Sanders, A. R., Williams, N., Wormley, B., Lasseter, V. K., Albus, M., Godard-Bauche, S., Alexander, M., Duan, J., O'Donovan, M. C., Walsh, D., O'Neill, A., Papadimitriou, G. N., Dikeos, D., Maier, W., Lerer, B., Campion, D., Cohen, D. R., Jay, M., Fanous, A., Eichhammer, P., Silverman, J. M., Norton, N., Zhang, N., Hakonarson, H., Gao, C., Citri, A., Hansen, M., Ripke, S., Dudbridge, F. & Holmans, P. A. (2012). Genome-wide association study of multiplex schizophrenia pedigrees. American Journal of Psychiatry, 169 (9), 963-973.


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. Withinfamily 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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