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

Polimanti, Renato, Peterson, Roseann E, Ong, Jue-Sheng, MacGregor, Stuart, Edwards, Alexis C, Clarke, Toni-Kim, Frank, Josef, Gerring, Zachary, Gillespie, Nathan A, Lind, Penelope A
et al (show 362 more authors) (2019) Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium. PSYCHOLOGICAL MEDICINE, 49 (7). pp. 1218-1226.

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<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.<h4>Conclusion</h4>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.

Item Type: Article
Uncontrolled Keywords: Alcohol consumption, alcohol dependence, genetic correlation, genome-wide association, major depression, Mendelian randomization
Depositing User: Symplectic Admin
Date Deposited: 19 Feb 2020 16:07
Last Modified: 19 Jan 2023 00:02
DOI: 10.1017/S0033291719000667
Open Access URL: https://www.biorxiv.org/content/10.1101/412098v1.f...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3075749