Shared genetic etiology between alcohol dependence and major depressive disorder

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 (~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, R2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R2=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, R2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R2=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, R2=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, R2=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.

Fig. 1

Polygenic risk score model fit. (a) GESGA target sample based on PGC-MDD2 (n=59 265 cases; n=112 092 controls); (b) PGC-MDD1 (n=8148 cases; n=7955 controls) discovery samples; (c) BoMa-MDD target sample based on PGC-MDD2 and (d) PGC-MDD1; and inset (e) non-PREDICT (left) and PREDICT (right) GESGA target subsamples based on PGC-MDD2. MDD, major depressive disorder; PGC, Psychiatric Genomics Consortium. ^#P<0.10; ^1*P<0.05; ^2*P<0.01; ^3*P<0.001; ^4*P<0.0001; ^5*P<0.00001.