TY - JOUR
T1 - Evidence of causal effect of major depression on alcohol dependence
T2 - Findings from the psychiatric genomics consortium
AU - Polimanti, Renato
AU - Peterson, Roseann E.
AU - Ong, Jue Sheng
AU - MacGregor, Stuart
AU - Edwards, Alexis C.
AU - Clarke, Toni Kim
AU - Frank, Josef
AU - Gerring, Zachary
AU - Gillespie, Nathan A.
AU - Lind, Penelope A.
AU - Maes, Hermine H.
AU - Martin, Nicholas G.
AU - Mbarek, Hamdi
AU - Medland, Sarah E.
AU - Streit, Fabian
AU - Agrawal, Arpana
AU - Edenberg, Howard J.
AU - Kendler, Kenneth S.
AU - Lewis, Cathryn M.
AU - Sullivan, Patrick F.
AU - Wray, Naomi R.
AU - Gelernter, Joel
AU - Derks, Eske M.
PY - 2019/5
Y1 - 2019/5
N2 - BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation.CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
AB - BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation.CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
KW - Alcohol consumption
KW - alcohol dependence
KW - genetic correlation
KW - genome-wide association
KW - major depression
KW - Mendelian randomization
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U2 - 10.1017/S0033291719000667
DO - 10.1017/S0033291719000667
M3 - Article
C2 - 30929657
VL - 49
SP - 1218
EP - 1226
JO - Psychological Medicine
JF - Psychological Medicine
SN - 0033-2917
IS - 7
ER -
