Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.
Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders.
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超过100万受试者的多元基因组关联荟萃分析确定了多种物质使用障碍的基因座。
DOI：
10.1038/s44220-023-00034-y
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发表时间：
2023-03
期刊：
影响因子：
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通讯作者：
Agrawal, Arpana
中科院分区：
文献类型：
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作者：
Hatoum, Alexander S;Colbert, Sarah M C;Johnson, Emma C;Huggett, Spencer B;Deak, Joseph D;Pathak, Gita;Jennings, Mariela V;Paul, Sarah E;Karcher, Nicole R;Hansen, Isabella;Baranger, David A A;Edwards, Alexis;Grotzinger, Andrew;Tucker-Drob, Elliot M;Kranzler, Henry R;Davis, Lea K;Sanchez-Roige, Sandra;Polimanti, Renato;Gelernter, Joel;Edenberg, Howard J;Bogdan, Ryan;Agrawal, Arpana
物质使用障碍的遗传倾向性可以解析为赋予一般或特定物质成瘾风险的位点。我们报告了一项多变量全基因组关联荟萃分析，该分析对已发表的关于酒精使用问题、烟草使用问题、大麻使用障碍和阿片类药物使用障碍的汇总统计数据进行了一般和物质特异性位点的分类，样本包括1,025,550名欧洲血统个体和92,630名非洲血统个体。一般成瘾危险因素（addiction-rf）有19个独立snp在全基因组显著（P < 5e-8），显示出高多基因性。在不同的祖先中，PDE4B是显著的（在其他基因中），表明多巴胺调节是一种跨物质脆弱性。成瘾-rf多基因风险评分与物质使用障碍、精神病理、躯体状况和与成瘾发病相关的环境有关。物质特异性基因座（酒精9个，烟草32个，大麻5个，类阿片1个）包括代谢和受体基因。这些发现提供了对物质使用障碍的遗传风险位点的深入了解，可以作为治疗目标。
Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.