T18. genetic contribution to the comorbidity between attention-deficit hyperactivity disorder and substance use disorders

Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. ADHD genetic and environmental factors may also contribute to the development of substance use disorders (SUDs). The current study aimed to systematically characterize the genetic architecture of ADHD-SUD comorbidity, investigating causal relationships and shared genetic mechanisms. Genome-wide association statistics were derived from iPSYCH, deCODE, and PGC cohorts for ADHD (Neff=51,568), and from Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for cannabis use disorder (CanUD, Neff=161,053), opioid use disorder (OUD, Neff=57,120), problematic alcohol use (PAU, Neff=502,272), and problematic tobacco use (PTU, Neff=270,120). Linkage Disequilibrium Score Regression was used for heritability and genetic correlation analysis. Genomic SEM was used to assess the association of the phenotypes with the underlying shared latent genetic factor. Bidirectional Mendelian randomization (MR) analyses were performed with the TwoSampleMR package. Genome-wide pleiotropy analyses were conducted with the PolarMorphism package. ADHD was positively genetically correlated with CanUD (rg=0.61, p=3.81 × 10-110), OUD (rg=0.34, p=2.55 × 10-5), PAU (rg=0.38, p=2.79 × 10-46), and PTU (rg=0.43, p=4.03 × 10-38). The Genomic SEM analysis showed that these pairwise genetic correlations can be summarized by two factors: one related to ADHD, CanUD, and PTU and the other to OUD and PAU. The MR analysis highlighted bi-directional relationships with PAU and PTU having a larger effect on ADHD than the reverse (PAU: betaADHD-outcome=0.56, pADHD-outcome=2.36 × 10-7; betaADHD-exposure=0.03, pADHD-exposure=0.02, PTU: betaADHD-outcome=0.28, pADHD-outcome=7.35 × 10-6; betaADHD-exposure=0.07, pADHD-exposure=3.25 × 10-5). A similar effect was found between ADHD and CanUD in both directions (betaADHD-outcome=0.38, pADHD-outcome=4.32 × 10-13; betaADHD-exposure=0.33, pADHD-exposure=2.75 × 10-11). The genome-wide pleiotropy analysis identified CADM2 rs62250713 as shared between ADHD and all SUDs (ppleiotropy=2.69 × 10-8). When analyzing ADHD pleiotropy with specific SUD, we found seven, one, and 28 pleiotropic variants for CanUD, PAU, and PTU, respectively. We provide comprehensive evidence on genetic relationships between ADHD with CanUD, OUD, PAU, and PTU. The potential causal effects of PAU and PTU on ADHD highlights the importance of ADHD screening in SUD patients, while the presence of shared pathogenic loci may support the identification of molecular target for ADHD-SUD drug development.