Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (N_cases = 20,686;N_effective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h²_SNP) and genetic correlations (r_g). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10⁻⁸) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10⁻¹⁰) and two OPRM1 variants (rs1799971, p = 4.92 × 10⁻⁰⁹; rs79704991, p = 1.11 × 10⁻⁰⁸; r² = 0.02). Rs1799971 (p = 4.91 × 10⁻⁰⁸) and another OPRM1 variant (rs9478500; p = 1.95 × 10⁻⁰⁸; r² = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h²_SNP was 12.75%, with strong r_g with CanUD (r_g = 0.82; p = 1.14 × 10⁻⁴⁷) and AUD (r_g = 0.77; p = 6.36 × 10⁻⁷⁸). The OUD-MTAG resulted in a GWAS N_equivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10⁻¹⁶) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10⁻¹³) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

尽管阿片类药物使用障碍 (OUD) 造成了巨大损失，但迄今为止 OUD 的全基因组关联研究 (GWAS) 几乎没有发现易感位点。我们对欧洲 (EUR) 和非洲 (AFR) 血统的个体进行了大规模的 OUD GWAS，通过对遗传相关物质使用障碍 (SUD) 进行 MTAG（GWAS 多特征分析）来优化遗传信息。荟萃分析包括七个队列：百万退伍军人计划、精神病学基因组学联盟、iPSYCH、FinnGen、Partners Biobank、BioVU 和耶鲁-宾夕法尼亚大学 3，结果总计N = 639,063（ N_例= 20,686；N_有效= 77,026）祖先。 OUD 病例被定义为终生 OUD 诊断，对照组为未知符合 OUD 标准的任何人。我们估计了 SNP 遗传力 (h ² _SNP ) 和遗传相关性 (r _g )。基于遗传相关性，我们对 OUD、酒精使用障碍 (AUD) 和大麻使用障碍 (CanUD) 进行了 MTAG。进行了留一法多基因风险评分 (PRS) 分析，以比较 OUD 和 OUD-MTAG PRS 作为耶鲁-宾夕法尼亚大学 OUD 病例状态的预测因子 3。EUR 荟萃分析确定了三个全基因组显着性 (GWS; p ≤ 5 × 10 ^{− 8} ) 先导 SNP — 一个位于FURIN (rs11372849； p = 9.54 × 10 ^{− 10} ) 和两个OPRM1变体 (rs1799971， p = 4.92 × 10 ^{− 09} ；rs79704991， p = 1.11 × 10 ^{− 08} ；r ² = 0.02）。 Rs1799971 (p = 4.91 × 10 ^{− 08} ) 和另一个OPRM1变体 (rs9478500; p = 1。95× ^{10-08 ；} r ² = 0.03）在跨血统荟萃分析中被确定。估计 h ² _SNP为 12.75%，CanUD 具有较强的 r _g (r _g = 0.82； p = 1.14 × 10 ^{− 47} ) 和 AUD (r _g = 0.77； p = 6.36 × 10 ^{− 78} )。 OUD-MTAG 产生了 GWAS N_等效值= 128,748 和 18 个独立的 GWS 位点，其中一些映射到先前与精神病或成瘾表型相关的基因或基因区域。 OUD-MTAG PRS 占 OUD 方差的 3.81%（beta = 0.61；se = 0.066； p = 2.00 × 10 ^{− 16} ），而 OUD-MTAG PRS 占 OUD 方差的 2.41%（beta = 0.45；se = 0.058； p = 2.90 × 10 ^{− 13} ）由 OUD PRS 解释。目前的研究确定了OPRM1中的 OUD 变异关联、与FURIN的单一变异关联以及 OUD-MTAG 中的 18 个 GWS 关联。 OUD 的遗传结构可能受到 OUD 特异性基因座和 SUD 共享基因座的影响。