RT Journal Article
T1 Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.
A1 Mullins, N
A1 Power, R A
A1 Fisher, H L
A1 Hanscombe, K B
A1 Euesden, J
A1 Iniesta, R
A1 Levinson, D F
A1 Weissman, M M
A1 Potash, J B
A1 Shi, J
A1 Uher, R
A1 Cohen-Woods, S
A1 Rivera, M
A1 Jones, L
A1 Jones, I
A1 Craddock, N
A1 Owen, M J
A1 Korszun, A
A1 Craig, I W
A1 Farmer, A E
A1 McGuffin, P
A1 Breen, G
A1 Lewis, C M
K1 Depression
K1 gene-environment interactions
K1 genetics
K1 polygenic risk scoring
AB 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. 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. 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. 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.
PB Cambridge University Press
YR 2015
FD 2015-19-22
LK http://hdl.handle.net/10668/9608
UL http://hdl.handle.net/10668/9608
LA en
NO Mullins N, Power RA, Fisher HL, Hanscombe KB, Euesden J, Iniesta R, et al. Polygenic interactions with environmental adversity in the aetiology of major depressive disorder. Psychol Med. 2016 Mar;46(4):759-70.
NO The RADIANT studies were funded by a joint grant from the UK Medical Research Council, GlaxoSmithKline (G0701420) and by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute  of Psychiatry, Psychology and Neuroscience, King’s College London. The GENDEP study was funded by a European Commission Framework 6 grant (EC contract ref.: LSHB-CT-2003-503428). The GenRED project was supported by National Institute of Mental Health (NIMH) R01 grants MH061686 (D.F.L.), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (J.B.P.), MH059541 (WA Scheftner) and MH060912 (M.M.W.). We acknowledge the contributions of Dr George S. Zubenko and Dr Wendy N. Zubenko, Department of Psychiatry,  University of Pittsburgh School of Medicine to the GenRED 1 project. The DGN study was supported by the NIMH (grant 5RC2MH089916 ).  N.M. and C.M.L. have received funding from the European Community’s Seventh Framework Programme under the Marie Curie Industry-Academia Partnership and  Pathways (grant 286213). H.L.F. is supported by an MQ Fellows Award (MQ14F40). R.U. is supported by the Canada Research Chairs programme (http://www.chairs-chaires.gc.ca/). We thank all individuals who participated in the RADIANT and GENDEP studies and all involved with data collection and management.
DS RISalud
RD Apr 7, 2025