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

Kember, RLORCID logo; Vickers-Smith, R; Xu, H; Toikumo, S; Niarchou, MORCID logo; Zhou, HORCID logo; Hartwell, EEORCID logo; Crist, RC; Rentsch, CTORCID logo; Million Veteran Program; +6 more...Davis, LK; Justice, ACORCID logo; Sanchez-Roige, SORCID logo; Kampman, KM; Gelernter, JORCID logo; Kranzler, HRORCID logo and (2022) Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction. Nature Neuroscience, 25 (10). pp. 1279-1287. ISSN 1097-6256 DOI: 10.1038/s41593-022-01160-z
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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.


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This is an author accepted manuscript version of an article accepted for publication and following peer review. Please be aware that minor differences may exist between this version and the final version if you wish to cite from it.
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