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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月7日

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  • Dongbing Lai,
  • Michael Zhang,
  • Nick Green,
  • Marco Abreu,
  • Tae-Hwi Schwantes-An,
  • Clarissa C. Parker,
  • Shanshan Zhang,
  • Fulai Jin,
  • Anna Sun,
  • Pengyue Zhang,
  • Howard J. Edenberg,
  • Yunlong Liu,
  • Tatiana Foroud

摘要

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.