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

Abstract

BackgroundDespite 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.MethodsLinkage 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).ResultsPositive 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.ConclusionThis 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.

Parental alcohol use disorder with and without other mental disorders and offspring alcohol use disorder

“…For instance, different patterns of concurrent or sequential mental disorder comorbidity might be present, so that neither the father's AUD nor the mental disorder interfered strongly with the environment in which the offspring grew up. Additionally, molecular genetic data support a causal influence of major depressive disorder (MDD) on alcohol dependence (48). The self-medication hypothesis could thus be consistent with our observations in that the father's AUD would be "caused" by his MDD.…”

Effect of alcohol use disorders and alcohol intake on the risk of subsequent depressive symptoms: a systematic review and meta‐analysis of cohort studies

“…Other common confounders, including physical health status and psychological comorbidity, have been reported to play important roles in the comorbidity of alcohol misuse and depression . Several studies using Mendelian randomization have failed to find a significant association between alcohol intake and subsequent depression. Consistent with our findings, this indicates that the association between alcohol intake and depressive symptoms is most probably attributed to the shared confounding factors, rather than the biological effects of alcohol.…”

Recent Efforts to Dissect the Genetic Basis of Alcohol Use and Abuse

“…Furthermore, it is also possible that the genetic overlap between AD and aspects of alcohol consumption are dependent on the specific patterns of drinking. For example, Polimanti et al (64) identified a positive genetic correlation between AD and alcohol drinking quantity (rg = 0.75), but not frequency.…”