TY - JOUR
T1 - Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder
AU - Arnau-Soler, Aleix
AU - Adams, Mark J.
AU - Hayward, Caroline
AU - Thomson, Pippa A.
AU - Porteous, David
AU - Campbell, Archie
AU - Smith, Blair H.
AU - Black, Corri
AU - Padmanabhan, Sandosh
AU - McIntosh, Andrew
AU - Wray, Naomi R.
AU - Ripke, Stephan
AU - Mattheisen, Manuel
AU - Trzaskowski, Maciej
AU - Byrne, Enda M.
AU - Abdellaoui, Abdel
AU - Agerbo, Esben
AU - Air, Tracy M.
AU - Andlauer, Till F.M.
AU - Bacanu, Silviu Alin
AU - Bækvad-Hansen, Marie
AU - Beekman, Aartjan T.F.
AU - Bigdeli, Tim B.
AU - Binder, Elisabeth B.
AU - Blackwood, Douglas H.R.
AU - Bryois, Julien
AU - Buttenschøn, Henriette N.
AU - Bybjerg-Grauholm, Jonas
AU - Cai, Na
AU - Castelao, Enrique
AU - Christensen, Jane Hvarregaard
AU - Clarke, Toni Kim
AU - Coleman, Jonathan R.I.
AU - Colodro-Conde, Lucía
AU - Couvy-Duchesne, Baptiste
AU - Craddock, Nick
AU - Crawford, Gregory E.
AU - Davies, Gail
AU - Deary, Ian J.
AU - Degenhardt, Franziska
AU - Grove, Jakob
AU - Hansen, Christine Søholm
AU - Hansen, Thomas F.
AU - Pedersen, Carsten Bøcker
AU - Pedersen, Marianne Giørtz
AU - Qvist, Per
AU - Yang, Jian
AU - Mors, Ole
AU - Mortensen, Preben Bo
AU - Børglum, Anders D.
AU - Generation Scotland
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
PY - 2018/12/20
Y1 - 2018/12/20
N2 - Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.
AB - Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.
KW - ALCOHOL-USE
KW - ANXIETY
KW - ASSOCIATION ANALYSIS
KW - GENETIC EPIDEMIOLOGY
KW - LIFE EVENTS
KW - METAANALYSIS
KW - NEUROTICISM
KW - PERCEIVED STRESS
KW - PERSONALITY
KW - PTP4A1-PHF3-EYS VARIANTS
UR - http://www.scopus.com/inward/record.url?scp=85058923883&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0209160
DO - 10.1371/journal.pone.0209160
M3 - Journal article
C2 - 30571770
AN - SCOPUS:85058923883
SN - 1932-6203
VL - 13
JO - PLOS ONE
JF - PLOS ONE
IS - 12
M1 - e0209160
ER -