Shared Genetic Etiology Between Alcohol Dependence and Major Depressive Disorder

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 PGCMDD1
(P-threshold=0.2, P=0.00014, R2=0.663%) metaanalyses;
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.