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Acknowledgments
DWB is supported by grants from the US National Institute on Aging T32-AG00029, P30 AG028716-08. SI received support from National Institute of Child Health & Human Development Grants HD061298 and HD077482, National Institute on Aging Grant AG032282, and the Jacobs Foundation and is grateful to the Yad Hanadiv Rothschild Foundation for the award of a Rothschild Fellowship.
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Appendix: Box 1. Examples of Type 1 and Type 2 GxE questions: the case of depression
Appendix: Box 1. Examples of Type 1 and Type 2 GxE questions: the case of depression
Type 1 GxE question example. Environmental stress exposure is a risk factor for depression, but the mechanism through which stress causes depression is unknown. Altered serotonergic signaling in brain is hypothesized as a mechanism through which stress causes depression, but this hypothesis is difficult to test experimentally in humans. The gene encoding the serotonin transporter (5HTT) contributes to the regulation of stress response in rodents [40]. A length polymorphism in that gene (5HTT-LPR) modifies its function [41, 42] and is associated with stress-dependent concentrations of serotonin in the cerebrospinal fluid of rhesus macaques [43] and with threat-related reactivity of the amygdala in humans [44]. On the basis of this evidence, one foundational GxE study used 5HTT-LPR as an instrument to measure individual differences in a difficult to observe biological substrate, serotonergic signaling in brain in response to stress [45]. The GxE analysis examined the interaction of stressful live events with 5HTT-LPR in predicting depression. Framed as a Type 1 GxE question, that analysis tested the hypothesis that environmental stress contributes to the pathogenesis of depression via effects on serotonergic signaling in brain.
Type 2 GxE question example. Depression is known to be heritable. But not all individuals genetically predisposed to depression manifest illness. Environmental exposures are hypothesized to modify the effect of a genetic liability on depression. Although GWAS of depression have not detected replicable associations at the level of individual SNPs, results from GWAS and from genome-wide complex trait analysis indicate substantial and highly polygenic genetic influence on depression [27, 46, 47]. On the basis of this evidence, a recent GxE analysis examined whether genetic liability to depression (as measured by a GWAS-derived polygenic score) was modified by exposure to stressful life events [34]. Framed as a Type 2 GxE question, that analysis tested the hypothesis that genetically vulnerable individuals may be especially likely to develop depression when exposed to stress.
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Belsky, D.W., Suppli, N.P. & Israel, S. Gene-environment interaction research in psychiatric epidemiology: a framework and implications for study design. Soc Psychiatry Psychiatr Epidemiol 49, 1525–1529 (2014). https://doi.org/10.1007/s00127-014-0954-5
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DOI: https://doi.org/10.1007/s00127-014-0954-5