Genome‐wide association analysis accounting for environmental factors through propensity‐score matching: Application to stressful live events in major depressive disorder

Abstract

Stressful life events are an established trigger for depression and may contribute to the heterogeneity within genome-wide association analyses. With depression cases showing an excess of exposure to stressful events compared to controls, there is difficulty in distinguishing between "true" cases and a "normal" response to a stressful environment. This potential contamination of cases, and that from genetically at risk controls that have not yet experienced environmental triggers for onset, may reduce the power of studies to detect causal variants. In the RADIANT sample of 3,690 European individuals, we used propensity score matching to pair cases and controls on exposure to stressful life events. In 805 case-control pairs matched on stressful life event, we tested the influence of 457,670 common genetic variants on the propensity to depression under comparable level of adversity with a sign test. While this analysis produced no significant findings after genome-wide correction for multiple testing, we outline a novel methodology and perspective for providing environmental context in genetic studies. We recommend contextualizing depression by incorporating environmental exposure into genome-wide analyses as a complementary approach to testing gene-environment interactions. Possible explanations for negative findings include a lack of statistical power due to small sample size and conditional effects, resulting from the low rate of adequate matching. Our findings underscore the importance of collecting information on environmental risk factors in studies of depression and other complex phenotypes, so that sufficient sample sizes are available to investigate their effect in genome-wide association analysis.

Genome-wide association study and polygenic risk score analysis for hearing measures in children

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Integrating NIMH Research Domain Criteria (RDoC) into depression research

“…Indeed, researchers now recognize that psychiatric disorders such as depression, as well as intermediate phenotypes or endophenotypes associated with depression, are likely impacted by the combined influence of multiple genes operating within specific biological pathways. Given this, researchers have begun to examine aggregate levels of influence across multiple genes and there is a call to scale this up to GWAS × environment analyses (e.g., Peyrot et al, 2014; Power et al, 2013; Thomas, 2010), which may help to resolve the previous null GWAS findings. In combination, what these studies suggest is that depression-relevant influences across multiple units of analysis cannot be understood without considering the environmental context.…”

Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis

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