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. 2019 May;49(7):1218-1226.
doi: 10.1017/S0033291719000667. Epub 2019 Apr 1.

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

Renato Polimanti  1 , Roseann E Peterson  2 , Jue-Sheng Ong  3 , Stuart MacGregor  3 , Alexis C Edwards  2 , Toni-Kim Clarke  4 , Josef Frank  5 , Zachary Gerring  6 , Nathan A Gillespie  2 , Penelope A Lind  7 , Hermine H Maes  2 , Nicholas G Martin  8 , Hamdi Mbarek  9 , Sarah E Medland  7 , Fabian Streit  5 ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Arpana Agrawal  10 , Howard J Edenberg  11 , Kenneth S Kendler  2 , Cathryn M Lewis  12 , Patrick F Sullivan  13 , Naomi R Wray  14 , Joel Gelernter  1 , Eske M Derks  6
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Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

Renato Polimanti et al. Psychol Med. 2019 May.

Abstract

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.

Keywords: Alcohol consumption; Mendelian randomization; alcohol dependence; genetic correlation; genome-wide association; major depression.

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Conflict of interest statement

Conflict of interest. 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. The other authors reported no biomedical financial interests or potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Genetic correlations of major depression (MD), alcohol dependence (AD), and alcohol consumption quantity (ACQ), and alcohol consumption frequency (ACF).
Fig. 2
Fig. 2
Single nucleotide polymorphism (SNP)-exposure (major depression (MD) associations, logOR) and SNP-outcome (alcohol dependence (AD) associations, logOR) coefficients used in the Mendelian randomization (MR) analysis. Error bars (95% CIs) are reported for each association.
See this image and copyright information in PMC

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