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Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Published online by Cambridge University Press:  19 August 2011

A. L. Collins ,
Y. Kim ,
P. Sklar ,
M. C. O'Donovan  and
P. F. Sullivan
A. L. Collins*
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
Y. Kim
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
P. Sklar
Affiliation:
Department of Psychiatry, Mt Sinai School of Medicine, New York, NY, USA
M. C. O'Donovan
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK
P. F. Sullivan*
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
*
(Email: [email protected]) [A.L.C.]
*Address for correspondence: P. F. Sullivan, M.D., FRANZCP, Department of Genetics, CB#7264, 5097 Genomic Medicine, University of North Carolina, Chapel Hill, NC 27599-7264, USA. (Email: [email protected]) [P.F.S.]
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Abstract

Background

Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).

Method

We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC).

Results

SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results.

Conclusions

We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.

Keywords

Candidate gene associationcomparative studygeneticsgenome-wide associationneurodevelopmentalschizophreniasynapse
Type
Original Articles
Information
Psychological Medicine , Volume 42 , Issue 3 , March 2012 , pp. 607 - 616
Copyright
Copyright © Cambridge University Press 2011

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