Disentangling the shared genetics of ADHD, cannabis use disorder and cannabis use and prediction of cannabis use disorder in ADHD
Nielsen, T. T.; Duan, J.; Levey, D. F.; Walters, G. B.; Johnson, E. C.; Thorgeirsson, T.; VA Million Veteran Program, ; Werge, T.; Mortensen, P. B.; Stefansson, H.; Stefansson, K.; Hougaard, D. M.; Agrawal, A.; Gelernter, J.; Grove, J.; Borglum, A. D.; Demontis, D.
Show abstract
Cannabis use disorder (CUD) and cannabis use (CU) are prevalent conditions cooccurring with ADHD, but not much is known about the underlying shared genetics. Here we perform cross-disorder GWAS meta-analyses of ADHD and CUD or CU to identify pleiotropic risk loci and evaluate differences in the genetics of ADHD-CUD and ADHD-CU, and subsequently we dissect the polygenic architecture of CUD comorbidity in ADHD in the iPSYCH cohort. There was a higher genetic overlap of ADHD and CUD than observed for ADHD and CU and we found a significant direct effect of ADHD genetic risk on CUD with only a minor part (12%) mediated by the genetics of CU. We identified 36 genome-wide significant loci for ADHD-CUD and 10 loci for ADHD-CU, with concordant direction of effect on the phenotypes. Three different approaches identified DRD2, which encodes the dopamine 2 receptor, as a risk gene for ADHD-CUD and, overall, ADHD-CUD risk genes were associated with high expression across several brain tissues and brain developmental stages, which was not observed for ADHD-CU genes. ADHD-CUD and ADHD-CU demonstrated similar genetic correlations with substance use phenotypes, while they differed significantly with respect to substance use disorder (SUD) phenotypes. ADHD-CUD individuals had significantly increased polygenic score (PGS) for psychiatric disorders compared to ADHD without CUD and increased burden of rare deleterious variants. Stratifying individuals with ADHD by their CUD-PGS revealed an absolute risk of 22% for comorbid CUD among the 20% of cases with the highest CUD-PGS, which was strikingly higher than the absolute risk of 1.6% observed among the 20% of controls with the highest CUD-PGS. Sex-specific analyses identified substantial differences in the absolute risk of comorbid CUD between males and females with ADHD, with a [~]10% higher CUD risk among males than females in the high-risk CUD-PGS group (24% risk for males and 14% risk for females).
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