In the last three years, five opioid use disorder (OUD) GWAS have yielded genome-wide significant loci (e.g., repulsive guidance molecule BMP co-receptor a (RGMA), cornichon family AMPA receptor auxiliary protein 3 (CNIH3) and potassium voltage-gated channel subfamily C member 1 (KCNC1))38–41 and identified potential biological pathways involved in OUD pathogenesis. However, the limited sample size of these studies did not permit investigation of the polygenic architecture of OUD. The PGC-SUD workgroup combined these GWAS datasets together with additional cohorts, comparing 4,503 opioid-dependence (OD) cases, 4,173 opioid-exposed (OE) controls, and 32,500 opioid-unexposed controls41. There were GWS loci (e.g., the SDCCAG8 SHH signalling and ciliogenesis regulator gene), and a different genetic-overlap pattern observed across the traits investigated. A PRS based on a GWAS of risk-tolerance42 was positively associated with OD (OD cases versus unexposed or exposed controls) and OE (exposed controls versus unexposed controls). A PRS based on a GWAS of neuroticism43 was positively associated with OD (OD cases versus unexposed controls and OD cases versus exposed controls) but not with opioid exposure (exposed versus unexposed controls). These analyses highlight the difference
