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Psychol Med. 2012 Mar;42(3):607-16. doi: 10.1017/S0033291711001607. Epub 2011 Aug 19.

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

Author information

1
Department of Genetics, University of North Carolina at Chapel Hill, NC 27599-7264, USA. collin@med.unc.edu

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.

PMID:
21854684
PMCID:
PMC4188923
DOI:
10.1017/S0033291711001607
[Indexed for MEDLINE]
Free PMC Article

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