美国宾夕法尼亚大学佩雷尔曼医学院Henry R. Kranzler团队近期取得重要工作进展，他们通过对阿片类药物使用障碍的跨种族元分析，发现了在与成瘾相关的脑区中具有主要影响的新基因座。相关研究成果2022年9月28日在线发表于《自然—神经科学》杂志上。

研究人员对百万老兵计划（N=425,944）中的OUD进行了跨种族元分析。除了在OPRM1和FURIN中已知的外显子变体外，研究小组还在RABEPK、FBXW4、NCAM1和KCNN1中发现了内含子变体。一项包含其他数据集的元分析在TSNARE1中发现了一个位点。研究人员总共鉴定了14个OUD基因座，其中12个是新发现的。研究发现127个性状具有显著的遗传相关性，包括精神障碍和其他药物滥用相关性状。唯一明显富集的细胞类型组是中枢神经系统，其基因表达富集于先前与药物使用障碍有关的脑区。这些发现增加了大家对急性脑畸形的生物学基础的了解，并进一步证明它是一种脑部疾病，这可能有助于减少耻辱感，并为应对阿片类药物的流行提供参考。

据了解，尽管阿片类药物使用障碍（OUD）的遗传性估计约为50%，但全基因组关联研究发现很少有全基因组显著性关联位点。

附：英文原文

Title: Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Author: Kember, Rachel L., Vickers-Smith, Rachel, Xu, Heng, Toikumo, Sylvanus, Niarchou, Maria, Zhou, Hang, Hartwell, Emily E., Crist, Richard C., Rentsch, Christopher T., Davis, Lea K., Justice, Amy C., Sanchez-Roige, Sandra, Kampman, Kyle M., Gelernter, Joel, Kranzler, Henry R.

Issue&Volume: 2022-09-28

Abstract: Despite an estimated heritability of ~50%, genome-wide association studies of opioid use disorder (OUD) have revealed few genome-wide significant loci. We conducted a cross-ancestry meta-analysis of OUD in the Million Veteran Program (N=425,944). In addition to known exonic variants in OPRM1 and FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1 and KCNN1. A meta-analysis including other datasets identified a locus in TSNARE1. In total, we identified 14 loci for OUD, 12 of which are novel. Significant genetic correlations were identified for 127 traits, including psychiatric disorders and other substance use-related traits. The only significantly enriched cell-type group was CNS, with gene expression enrichment in brain regions previously associated with substance use disorders. These findings increase our understanding of the biological basis of OUD and provide further evidence that it is a brain disease, which may help to reduce stigma and inform efforts to address the opioid epidemic.

DOI: 10.1038/s41593-022-01160-z

Source: https://www.nature.com/articles/s41593-022-01160-z