Elevated polygenic liability to MDD in our sample was associated with increasing problematic use of alcohol, cocaine, nicotine, and cannabis, in-line with prior twin studies suggesting MDD shares genetic liability with alcohol (Prescott et al., 2000), nicotine (Edwards et al., 2011), and cannabis use (Lynskey et al., 2004). Associations between MDD PRS and alcohol and cocaine dependence remained even when controlling for GENSUB. Prior genomewide studies of MDD with comorbid alcohol and cocaine dependence have uncovered significant or near-significant overlapping regions/variants contributing to MDD alone and to MDD with a comorbid SUD, as well as some regions/variants contributing to a combined MDD and SUD phenotype only (Yang et al., 2011; Edwards et al., 2012). Taken together, these parallel lines of evidence suggest that relationships between MDD and alcohol and cocaine dependence are substance-specific.
