As in our prior study18, we estimated a single factor model, scaled the variance of addiction-rf to 1, and allowed loadings to be estimated freely. The single factor model that loaded on Opioid Use Disorder (OUD; Neffective = 30,443), Problematic Alcohol Use (PAU; Neffective=300,789), Problematic Tobacco Use (PTU; Neffective = 270,120), and Cannabis Use Disorder (CUD; Neffective = 46,351) fit the data well (χ2(1) = .017, p = 0.895, CFI = 1, SRMR = 0.002). The latent factor loaded significantly on all indicators (standardized loadings on OUD = 0.83, PAU= 0.58, PTU = 0.36, CUD = 0.93 see Supplemental Figure 1 for full model). The addiction-rf was associated with 19 independent (r2< 0.1) genome-wide significant (GWS) SNPs that mapped to 17 genomic risk loci (Figure 1; Table 1; Supplemental Table 1 for lead SNPs and Supplemental Table 2 for genomic risk loci). The most significant SNP (rs6589386, p=2.9e-12) was intergenic, but closest to DRD2, which was GWS in gene-based analyses (p=7.9e-12; Supplemental Table 3). Further, rs6589386 was an expression quantitative trait locus (eQTL) for DRD2 in the cerebellum, and Hi-C analyses (in FUMA)23 revealed that the variant made chromatin contact with the promoter of the gene (Supplemental Figure 2).
