Annis Aubrey C, Gunaseelan Vidhya, Smith Albert V, Abecasis Gonçalo R, Larach Daniel B, Zawistowski Matthew, Frangakis Stephan G, Brummett Chad M
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
Genet Epidemiol. 2025 Jan;49(1):e22588. doi: 10.1002/gepi.22588. Epub 2024 Oct 9.
Persistent opioid use after surgery is a common morbidity outcome associated with subsequent opioid use disorder, overdose, and death. While phenotypic associations have been described, genetic associations remain unidentified. Here, we conducted the largest genetic study of persistent opioid use after surgery, comprising ~40,000 non-Hispanic, European-ancestry Michigan Genomics Initiative participants (3198 cases and 36,321 surgically exposed controls). Our study primarily focused on the reproducibility and reliability of 72 genetic studies of opioid use disorder phenotypes. Nominal associations (p < 0.05) occurred at 12 of 80 unique (r < 0.8) signals from these studies. Six occurred in OPRM1 (most significant: rs79704991-T, OR = 1.17, p = 8.7 × 10), with two surviving multiple testing correction. Other associations were rs640561-LRRIQ3 (p = 0.015), rs4680-COMT (p = 0.016), rs9478495 (p = 0.017, intergenic), rs10886472-GRK5 (p = 0.028), rs9291211-SLC30A9/BEND4 (p = 0.043), and rs112068658-KCNN1 (p = 0.048). Two highly referenced genes, OPRD1 and DRD2/ANKK1, had no signals in MGI. Associations at previously identified OPRM1 variants suggest common biology between persistent opioid use and opioid use disorder, further demonstrating connections between opioid dependence and addiction phenotypes. Lack of significant associations at other variants challenges previous studies' reliability.
术后持续使用阿片类药物是一种常见的发病结果，与随后的阿片类药物使用障碍、过量使用及死亡相关。虽然已经描述了表型关联，但基因关联仍未明确。在此，我们开展了术后持续使用阿片类药物的最大规模基因研究，纳入了约40000名非西班牙裔、欧洲血统的密歇根基因组计划参与者（3198例病例和36321例接受手术的对照）。我们的研究主要聚焦于72项阿片类药物使用障碍表型基因研究的可重复性和可靠性。在这些研究的80个独特（r<0.8）信号中，有12个出现了名义关联（p<0.05）。其中6个出现在OPRM1基因中（最显著的为rs79704991-T，OR=1.17，p=8.7×10），有2个在多重检验校正后仍显著。其他关联包括rs640561-LRRIQ3（p=0.015）、rs4680-COMT（p=0.016）、rs9478495（p=0.017，基因间区域）、rs10886472-GRK5（p=0.028）、rs9291211-SLC30A9/BEND4（p=0.043）以及rs112068658-KCNN1（p=0.048）。两个被高度引用的基因OPRD1和DRD2/ANKK1在密歇根基因组计划中未出现信号。先前确定的OPRM1变体的关联表明术后持续使用阿片类药物与阿片类药物使用障碍之间存在共同生物学机制，进一步证明了阿片类药物依赖与成瘾表型之间的联系。其他变体缺乏显著关联对先前研究的可靠性提出了挑战。
