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Foo, Jerome C.; Streit, Fabian; Treutlein, Jens; Ripke, Stephan; Witt, Stephanie H.; Strohmaier, Jana; Degenhardt, Franziska; Forstner, Andreas J.; Hoffmann, Per; Soyka, Michael; Dahmen, Norbert; Scherbaum, Norbert; Wodarz, Norbert; Heilmann-Heimbach, Stefanie; Herms, Stefan; Cichon, Sven; Preuss, Ulrich; Gäbel, Wolfgang; Ridinger, Monika; Hoffmann, Sabine; Schulze, Thomas G.; Maier, Wolfgang; Zill, Peter; Müller-Myhsok, Bertram; Ising, Marcus; Lucae, Susanne; Nöthen, Markus M.; Mann, Karl; Kiefer, Falk; Rietschel, Marcella; Frank, Josef (2018): Shared genetic etiology between alcohol dependence and major depressive disorder. In: Psychiatric Genetics, Vol. 28, No. 4: pp. 66-70
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Abstract

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.