Genome-wide meta-analyses of cross substance use disorders in diverse populations.

Substance use disorders (SUDs, including alcohol, cannabis, opioids, and tobacco) represent significant public health challenges. The estimated heritability of SUDs is ~50% and many individuals experience multiple SUDs concurrently. Studies have demonstrated the existence of genes shared across multiple SUDs, and identifying these SUD-shared genes is critical to developing novel prevention and treatment strategies. Here, we conducted the largest cross SUD meta-analysis to date to identify SUD-shared genes using samples genetically similar to 1000 Genomes Project European (1kg-EUR-like), African (1kg-AFR-like), and American mixed (1kg-AMR-like) populations. We defined variants that had the same direction of effects across different SUDs (i.e., concordant variants) as SUD-shared. In total, we identified 220 loci, including 40 novel loci that were not reported as SUD-associated in previous genome-wide association studies. Through gene-based analyses, gene mapping, and gene prioritization, we identified 785 SUD-shared genes. These genes are highly expressed in the amygdala, cortex, hippocampus, hypothalamus, and thalamus; and are primarily highly expressed in neuronal cells, suggesting that more brain regions may be involved in SUDs than previously reported. Concordant variants explained 56-96% of the SNP-heritability of each SUD in the 1kg-EUR-like sample. Furthermore, the top 10% of individuals in the 1kg-EUR-like and 1kg-AMR-like samples with the highest polygenic scores had odds ratios ranging from 1.95-2.87 to develop SUDs, and these polygenic scores could potentially be used to identify high-risk individuals. Lastly, using a real-world dataset, we identified seven SUD-shared genes targeting drugs that may be repurposed for treating SUDs, particularly in those suffering from comorbid SUDs.