The Penn Medicine BioBank (PMBB) contains the genetic information of 57,170 individuals linked to their electronic health records (EHRs) which store information on a patient’s diagnoses over time including substance abuse disorders (SUDs). Given that SUDs are highly heritable and polygenic, polygenic risk scores (PRS)—weighted sums of an individual’s genetic variants—are a method for estimating one’s genetic liability.

We generated PRS for tobacco use disorder (TUD), alcohol use disorder (AUD), opioid use disorder (OUD), and cannabis use disorder (CanUD) using summary statistics from publicly available genome-wide association studies (GWAS). PRS was then calculated using PRS-CS and applied to individuals in the PMBB using PLINK. We evaluated primary associations between each PRS and its corresponding phenotype and we defined phenotype cases by 1+ inpatient International Classification of Disease (ICD) code or 2+ outpatient ICD code. We then conducted a phenome-wide association study (PheWAS) to discover the relationship between PRS and other clinical phenotypes.

Primary phenotype associations were observed for PRSTUD (EUR and AFR), EUR PRSAUD, and EUR PRSCanUD (p < 0.05). PheWAS results revealed that EUR PRSAUD had significant positive associations with 15 phenotypes including TUD (p=2.7x10-41) and anxiety disorders (p=7.3x10-12) . EUR PRSCanUD, EUR PRSTUD, and AFR PRSTUD also had significant positive associations with TUD (p=5.9x10-38, p=8.0x10-47, and p=3.6x10-5, respectively). EUR PRSCanUD also had 17 more positive associations with different phenotypes including anxiety disorders (p=1.9x10-18), mood disorders (p=1.2x10-14), and viral hepatitis C (p=7.9x10-12). EUR PRSTUD also had positive associations with 31 more phenotypes including chronic airway obstruction (p=9.0x10-25), alongside 26 negative associations, most notably being benign neoplasm of skin (p=3.7x10-24).

These findings support the highly polygenic nature of SUDs and demonstrate shared genetic liability with other psychiatric and clinical phenotypes.