Genetic liability to addiction underlies comorbid bipolar and substance use disorders.
BACKGROUND Bipolar disorder (BIP) frequently co-occurs with heightened substance use (SU) and substance use disorders (SUDs). Although the strong co-occurrence of these heritable traits points to shared genetic susceptibility, the extent to which there are differences in how SU and SUD overlap with BIP genetic architecture remains unclear. METHODS We quantified the polygenic overlap between BIP and SUDs (alcohol, cannabis, opioid, and tobacco), and BIP and SU traits (drinks per week, lifetime cannabis use, prescription opioid use, and smoking initiation) using GWAS summary statistics and trivariate MiXeR. We then isolated the general and unique genetic contributions of SUD and SU using GWAS-by-subtraction via Genomic SEM. Next, we tested associations between polygenic risk scores derived from these latent factors and diagnostic and behavioral outcomes in the Norwegian Mother, Father and Child Cohort Study. Finally, we applied GSA-MiXeR to explore pleiotropic pathway enrichment shared between the latent factors and BIP. RESULTS We found extensive polygenic overlap between traits, with SUDs being more genetically correlated with BIP than SU traits. The unique SUD factor correlated positively with psychiatric disorders, whereas unique SU correlated negatively. PRS for BIP, shared SUD/SU, and unique SUD were significantly associated with BIP, SUD, and comorbid SUD-BIP; PRS for unique SU was only associated with self-reported lifetime SU. GSA-MiXeR revealed richer gene-set enrichment for SUD/BIP than SU/BIP implicating dopamine signaling and interneuron function. CONCLUSION By dissecting the genetic liability to SUD and SU and investigating their relationship with BIP we find a genetic signature correlated with substance dependence but not substance use more broadly.