Abstract
BackgroundIn psychiatric genetics research, the volume of ambivalent findings on gene-environment interactions (G x E) is growing at an accelerating pace. In response to the surging suspicions of systematic distortion, we challenge the notion of chance capitalization as a possible contributor. Beyond qualifying multiple testing as a mere methodological issue that, if uncorrected, leads to chance capitalization, we advance towards illustrating the potential benefits of multiple tests in understanding equivocal evidence in genetics literature.MethodWe focused on the interaction between the serotonin-transporter-linked promotor region (5-HTTLPR) and childhood adversities with regard to depression. After testing 2160 interactions with all relevant measures available within the Dutch population study of adolescents TRAILS, we calculated percentages of significant (p < .05) effects for several subsets of regressions. Using chance capitalization (i.e. overall significance rate of 5% alpha and randomly distributed findings) as a competing hypothesis, we expected more significant effects in the subsets of regressions involving: 1) interview-based instead of questionnaire-based measures; 2) abuse instead of milder childhood adversities; and 3) early instead of later adversities. Furthermore, we expected equal significance percentages across 4) male and female subsamples, and 5) various genotypic models of 5-HTTLPR.ResultsWe found differences in the percentages of significant interactions among the subsets of analyses, including those regarding sex-specific subsamples and genetic modeling, but often in unexpected directions. Overall, the percentage of significant interactions was 7.9% which is only slightly above the 5% that might be expected based on chance.ConclusionTaken together, multiple testing provides a novel approach to better understand equivocal evidence on G x E, showing that methodological differences across studies are a likely reason for heterogeneity in findings - but chance capitalization is at least equally plausible.
Highlights
In psychiatric genetics, the volume of studies examining gene-environment interactions (G x E) is increasing at an accelerating pace [1]
Multiple testing provides a novel approach to better understand equivocal evidence on G x E, showing that methodological differences across studies are a likely reason for heterogeneity in findings - but chance capitalization is at least plausible
In addition to chance capitalization, we explored the option that inconsistencies in G x E findings arise from differences in assessments, severity of the adversity, and timing of the adversity
Summary
The volume of studies examining gene-environment interactions (G x E) is increasing at an accelerating pace [1]. Inspired by Ioannidis and colleagues, we aimed to explore multiple testing within individual studies as a plausible explanation for heterogeneity of findings in G x E research on psychiatric disorders. The test result indicates whether or not the null hypothesis should be rejected. One or more significant G x E findings are to be expected as well: the risk of a false positive (i.e. incorrectly rejected null hypothesis) rises exponentially when testing multiple models with the commonly used hypothesis testing approach. The volume of ambivalent findings on gene-environment interactions (G x E) is growing at an accelerating pace. Beyond qualifying multiple testing as a mere methodological issue that, if uncorrected, leads to chance capitalization, we advance towards illustrating the potential benefits of multiple tests in understanding equivocal evidence in genetics literature.
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