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.
|Authors||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; Maes, Hermine H; Martin, Nicholas G; Mbarek, Hamdi; Medland, Sarah E; Streit, Fabian; , ; Agrawal, Arpana; Edenberg, Howard J; Kendler, Kenneth S; Lewis, Cathryn M; Sullivan, Patrick F; Wray, Naomi R; Gelernter, Joel; Derks, Eske M|
|Grant ID||K01 MH113848|
|Funding Body||NIMH NIH HHS|