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. 2017 Nov 15;82(10):702-708.
doi: 10.1016/j.biopsych.2017.06.033. Epub 2017 Jul 13.

No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes

Emma C Johnson  1 , Richard Border  2 , Whitney E Melroy-Greif  3 , Christiaan A de Leeuw  4 , Marissa A Ehringer  5 , Matthew C Keller  2
Affiliations

No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes

Emma C Johnson et al. Biol Psychiatry. .

Abstract

Background: A recent analysis of 25 historical candidate gene polymorphisms for schizophrenia in the largest genome-wide association study conducted to date suggested that these commonly studied variants were no more associated with the disorder than would be expected by chance. However, the same study identified other variants within those candidate genes that demonstrated genome-wide significant associations with schizophrenia. As such, it is possible that variants within historic schizophrenia candidate genes are associated with schizophrenia at levels above those expected by chance, even if the most-studied specific polymorphisms are not.

Methods: The present study used association statistics from the largest schizophrenia genome-wide association study conducted to date as input to a gene set analysis to investigate whether variants within schizophrenia candidate genes are enriched for association with schizophrenia.

Results: As a group, variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes. While a small subset of candidate genes did appear to be significantly associated with schizophrenia, these genes were not particularly noteworthy given the large number of more strongly associated noncandidate genes.

Conclusions: The history of schizophrenia research should serve as a cautionary tale to candidate gene investigators examining other phenotypes: our findings indicate that the most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.

Keywords: Candidate genes; Complex traits; GWAS; Gene set analysis; Genome-wide association study; SNP; Schizophrenia; Single nucleotide polymorphism.

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Conflict of interest statement

FINANCIAL DISCLOSURES

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1. Quantile-quantile plot of the −log10 p-values from the 25 most-studied candidate genes
Observed gene-level −log10 p-values from MAGMA are plotted on the y-axis, with expected −log10 p-values plotted on the x-axis. Points are heat map colored according to the number of times each gene has been studied, and the vertical green lines are bootstrapped 95% confidence intervals.
See this image and copyright information in PMC

Comment in

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