Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders
Dóra Koller, Marina Mitjans, Manuela R. Kouakou, Eleni Friligkou, Brenda Cabrera‐Mendoza, Joseph D. Deak, Natalia Llonga, Gita A. Pathak, Brendan Stiltner, Solveig Løkhammer, Daniel F. Levey, Hang Zhou, Alexander S. Hatoum, Rachel L. Kember, Henry R. Kranzler, Murray B. Stein, Roser Corominas, Ditte Demontis, María Soler Artigas, Josep Antoni Ramos‐Quiroga, Joel Gelernter, Marta Ribasès, Bru Cormand, Renato Polimanti
Abstract
We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff=51,568), 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=97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. PAU and PTU had a larger causal effect on ADHD than the reverse in the two-sample Mendelian randomization analyses. Conversely, similar effect sizes were found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.