Polygenic interactions with environmental adversity in the aetiology of major depressive disorder - PubMed (original) (raw)

doi: 10.1017/S0033291715002172. Epub 2015 Nov 3.

R A Power 1, H L Fisher 1, K B Hanscombe 2, J Euesden 1, R Iniesta 1, D F Levinson 3, M M Weissman 4, J B Potash 5, J Shi 6, R Uher 1, S Cohen-Woods 7, M Rivera 1, L Jones 8, I Jones 9, N Craddock 9, M J Owen 9, A Korszun 10, I W Craig 1, A E Farmer 1, P McGuffin 1, G Breen 1, C M Lewis 1

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Polygenic interactions with environmental adversity in the aetiology of major depressive disorder

N Mullins et al. Psychol Med. 2016 Mar.

Abstract

Background: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.

Method: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.

Results: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.

Conclusions: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Keywords: Depression; gene-environment interactions; genetics; polygenic risk scoring.

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Figures

Fig. 1.

Fig. 1.

Polygenic risk scores (PRS) for major depressive disorder and multiplicative interactions with stressful life events (SLEs) used to predict depression in the RADIANT UK sample. The y-axis indicates Nagelkerke's pseudo-_R_2, a measure of the variance explained. On the x-axis the nine p value thresholds used to select single nucleotide polymorphisms in the discovery phase are plotted left to right. depSLEs, Dependent SLEs; indepSLEs, independent SLEs; _p_T,p value threshold. * p < 0.005. For a colour figure, see the online version.

Fig. 2.

Fig. 2.

Polygenic risk scores (PRS) for major depressive disorder and multiplicative interaction with childhood trauma (CT) used to predict depression in the RADIANT UK sample. The y-axis indicates Nagelkerke's pseudo-_R_2, a measure of the variance explained. On the x-axis the nine p value thresholds used to select single nucleotide polymorphisms in the discovery phase are plotted left to right. _p_T, p value threshold. * p < 0.005. For a colour figure, see the online version.

Fig. 3.

Fig. 3.

Multiplicative interaction between standardized polygenic risk score for major depressive disorder (MDD) based on _p_T < 0.05 and categories of childhood trauma. Shaded circles are cases and open circles are controls. _p_T, p value threshold. For a colour figure, see the online version.

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