Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees

Levinson, Douglas F. ; Shi, Jianxin ; Wang, Kai ; Oh, Sang ; Riley, Brien ; Pulver, Ann E. ; Wildenauer, Dieter B. ; Laurent, Claudine ; Mowry, Bryan J. ; Gejman, Pablo V. ; Owen, Michael J. ; Kendler, Kenneth S. ; Nestadt, Gerald ; Schwab, Sibylle G. ; Mallet, Jacques ; Nertney, Deborah ; Sanders, Alan R. ; Williams, Nigel M. ; Wormley, Brandon ; Lasseter, Virginia K. ; Albus, Margot ; Godard-Bauché, Stephanie ; Alexander, Madeline ; Duan, Jubao ; O’Donovan, Michael C.

; Walsh, Dermot ; O’Neill, Anthony

; Papadimitriou, George N. ; Dikeos, Dimitris ; Maier, Wolfgang ; Lerer, Bernard ; Campion, Dominique ; Cohen, David ; Jay, Maurice ; Fanous, Ayman ; Eichhammer, Peter ; Silverman, Jeremy M. ; Norton, Nadine ; Zhang, Nancy ; Hakonarson, Hakon ; Gao, Cynthia ; Citri, Ami ; Hansen, Mark

; Ripke, Stephan ; Dudbridge, Frank ; Holmans, Peter A.

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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-cortrol 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: Mary 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 researcher; should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

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