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-Bauche, 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, The Schizophrenia Psychiatric GWAS Consortium, Dudbridge, Frank and Holmans, Peter A. (2012) Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees. American Journal of Psychiatry, 169 9: 963-973. doi:10.1176/appi.ajp.2012.11091423

Author 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-Bauche, 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
The Schizophrenia Psychiatric GWAS Consortium
Dudbridge, Frank
Holmans, Peter A.
Total Author Count Override 237
Title Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees
Journal name American Journal of Psychiatry   Check publisher's open access policy
ISSN 0002-953X
Publication date 2012-09-01
Sub-type Article (original research)
DOI 10.1176/appi.ajp.2012.11091423
Volume 169
Issue 9
Start page 963
End page 973
Total pages 11
Place of publication Arlington, VA, United States
Publisher American Psychiatric Publishing
Collection year 2013
Language eng
Formatted 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).

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.

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.

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.
Keyword Susceptibility loci
Multicenter linkage
Common variants
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2013 Collection
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
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