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Shared genetic etiology between alcohol dependence and major depressive disorder
Foo, J. C., Streit, F., Treutlein, J., Ripke, S., Witt, S. H., Strohmaier, J., Degenhardt, F., Forstner, A. J., Hoffmann, P., Soyka, M., Dahmen, N., Scherbaum, N., Wodarz, N., Heilmann-heimbach, S., Herms, S., Cichon, S., Preuss, U., Gaebel, W., Ridinger, M., ... Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2018). Shared genetic etiology between alcohol dependence and major depressive disorder. Psychiatric Genetics, 28(4), 66-70. https://doi.org/10.1097/YPG.0000000000000201
The clinical comorbidity of alcohol dependence (AD) and major depressive disorder (MDD) is well established, whereas genetic factors influencing co-occurrence remain unclear. A recent study using polygenic risk scores (PRS) calculated based on the first-wave Psychiatric Genomics Consortium MDD meta-analysis (PGC-MDD1) suggests a modest shared genetic contribution to MDD and AD. Using a (approximate to 10 fold) larger discovery sample, we calculated PRS based on the second wave (PGC-MDD2) of results, in a severe AD case-control target sample. We found significant associations between AD disease status and MDD-PRS derived from both PGC-MDD2 (most informative P-threshold=1.0, P=0.00063, R-2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R-2=0.663%) meta-analyses; the larger discovery sample did not yield additional predictive power. In contrast, calculating PRS in a MDD target sample yielded increased power when using PGC-MDD2 (P-threshold=1.0, P=0.000038, R-2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R-2=0.81%). Furthermore, when calculating PGC-MDD2 PRS in a subsample of patients with AD recruited explicitly excluding comorbid MDD, significant associations were still found (n=331; P-threshold=1.0, P=0.042, R-2=0.398%). Meanwhile, in the subset of patients in which MDD was not the explicit exclusion criteria, PRS predicted more variance (n=999; P-threshold=1.0, P=0.0003, R-2=0.693%). Our findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors. Larger target samples are needed to reduce noise and take advantage of increasing discovery sample size.
