Identifying genetic loci and phenomic associations of substance use traits: A multi‐trait analysis of GWAS (MTAG) study

Abstract Background and Aims Genome‐wide association studies (GWAS) of opioid use disorder (OUD) and cannabis use disorder (CUD) have lagged behind those of alcohol use disorder (AUD) and smoking, where many more loci have been identified. We sought to identify novel loci for substance use traits (SUTs) in both African‐ (AFR) and European‐ (EUR) ancestry individuals to enhance our understanding of the traits’ genetic architecture. Design We used multi‐trait analysis of GWAS (MTAG) to analyze four SUTs in EUR subjects (OUD, CUD, AUD and smoking initiation [SMKinitiation]), and three SUTs in AFR subjects (OUD, AUD and smoking trajectory [SMKtrajectory]). We conducted gene‐set and protein–protein interaction analyses and calculated polygenic risk scores (PRS) in two independent samples. Setting This study was conducted in the United States. Participants A total of 5692 EUR and 4918 AFR individuals in the Yale‐Penn sample and 29 054 EUR and 10 265 AFR individuals in the Penn Medicine BioBank sample. Findings MTAG identified genome‐wide significant (GWS) single nucleotide polymorphisms (SNPs) for all four traits in EUR: 41 SNPs in 36 loci for OUD; 74 SNPs in 60 loci for CUD; 63 SNPs in 52 loci for AUD; and 183 SNPs in 144 loci for SMKinitiation. MTAG also identified GWS SNPs in AFR: 2 SNPs in 2 loci for OUD; 3 SNPs in 3 loci for AUD; and 1 SNP in 1 locus for SMKtrajectory. In the Yale‐Penn sample, the MTAG‐derived PRS consistently yielded more significant associations with both the corresponding substance use disorder diagnosis and multiple related phenotypes than the GWAS‐derived PRS. Conclusions Multi‐trait analysis of genome‐wide association studies boosted the number of loci found for substance use traits, identifying genes not previously linked to any substance, and increased the power of polygenic risk scores. Multi‐trait analysis of genome‐wide association studies can be used to identify novel associations for substance use, especially those for which the samples are smaller than those for historically legal substances.