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

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.

Fig. 1 |. Manhattan and quantile–quantile plot for cross-ancestry meta-analysis of opioid use disorder (N_cases = 31,480 and N_controls = 394,484).

Meta-analyses with effective sample size weighting were performed in METAL. The nearest protein-coding gene (<1 Mb) in each locus is labeled. [] represents an intergenic locus. The dashed line indicates GWS after correction for multiple testing (P < 5 × 10⁻⁸).

Fig. 2 |. Enrichment of opioid use disorder in the brain.

a, Partitioning heritability enrichment analyses using LDSC show enrichment for OUD in the CNS. The dashed black lines indicate Bonferroni-corrected significance (P < 0.005). b, Heritability enrichment analyses for gene expression using GTEx data show enrichment for OUD in brain regions previously associated with addiction. c, Predicted gene expression using S-PrediXcan identified genes with differential expression in brain regions. Color of circle indicates downregulation (blue) or upregulation (red). Size of circle indicates −log₁₀P. Bonferroni correction was applied within each tissue conditioned on the number of genes tested.

Fig. 3 |. Phenotypic spectrum associated with opioid use disorder.

a, Genetic correlation analyses showed multiple traits significantly genetically correlated with OUD following Bonferroni correction (P < 1.25 × 10⁻³; red bars indicate positively correlated traits, while blue bars indicate negatively correlated traits). MR analyses identify causal associations between OUD and other traits (red arrows denote a positive causal association, blue arrows denote a negative causal association). b,c, PheWAS results in BioVU (b) and Yale-Penn (c) datasets. All phenotypes significant at an FDR of q < 0.05 are plotted. In b, all phenotypes that passed Bonferroni correction (P < 3.7 × 10⁻⁵) are labeled. For readability, in c, only the top three traits within each group that passed Bonferroni correction (P < 7.9 × 10⁻⁵) are labeled. Circle size denotes effect size. ASPD, antisocial personality disorder; PTSD, post-traumatic stress disorder.

Fig. 4 |. Genomic SEM analysis of ouD with other substance use traits and psychiatric disorders.

Analysis of OUD with PAU, problematic alcohol use; CUD, cannabis use disorder; SMK, ever smoked regularly; SCZ, schizophrenia; BIP, bipolar disorder; MDD, major depressive disorder; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; TS, Tourette’s syndrome; and OCD, obsessive-compulsive disorder identified four factors. Factor loadings for each trait are depicted by arrows between the trait and the factor. Correlation between factors is indicated by arrows between the factors. Residual variance for each trait is indicated by the U-circles. Standard errors are depicted in parentheses.