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. 2024 Mar:333:115758.
doi: 10.1016/j.psychres.2024.115758. Epub 2024 Feb 3.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders

Dora Koller  1 , Marina Mitjans  2 , Manuela Kouakou  3 , Eleni Friligkou  4 , Brenda Cabrera-Mendoza  4 , Joseph D Deak  4 , Natalia Llonga  5 , Gita A Pathak  4 , Brendan Stiltner  4 , Solveig Løkhammer  6 , Daniel F Levey  4 , Hang Zhou  4 , Alexander S Hatoum  7 , Rachel L Kember  8 , Henry R Kranzler  8 , Murray B Stein  9 , Roser Corominas  10 , Ditte Demontis  11 , María Soler Artigas  12 , Josep Antoni Ramos-Quiroga  13 , Joel Gelernter  14 , Marta Ribasés  12 , Bru Cormand  10 , Renato Polimanti  15
Affiliations

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders

Dora Koller et al. Psychiatry Res. 2024 Mar.

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. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was 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.

Keywords: Attention-deficit hyperactivity disorder; Mendelian randomization; Pleiotropy; Polygenic risk scoring; Substance use disorders.

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Conflict of interest statement

Declaration of competing interest Dr. Polimanti reports a research grant from Alkermes. Drs. Polimanti and Gelernter are paid for their editorial work in the journal Complex Psychiatry. Drs. Gelernter and Kranzler hold US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued January 26, 2021. Dr. Kranzler is a member of advisory boards for Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, and Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. Drs. Gelernter and Kranzler hold U.S. patent 10,900,082 titled: "Genotype-guided dosing of opioid agonists," issued 26 January 2021. Dr. Demontis has received speaker fees from Medice Nordic. The other authors declare no competing interests.

Figures

Figure 1.
Figure 1.
Genetic correlations between attention-deficit hyperactivity disorder (ADHD) and cannabis use disorder (CanUD), opioid use disorder (OUD), problematic alcohol use (PAU), and problematic tobacco use (PTU).
Figure 2.
Figure 2.
Genomic structural equation modeling of attention-deficit hyperactivity disorder (ADHD) and cannabis use disorder (CanUD), opioid use disorder (OUD), problematic alcohol use (PAU), and problematic tobacco use (PTU). Values correspond to loadings with standard error.
Figure 3.
Figure 3.
Bi-directional two-sample Mendelian randomization analysis using attention-deficit hyperactivity disorder (ADHD) as both exposure and outcome. Effect size and 95% confidence intervals are reported for the inverse variance-weighted effect estimates. ADHD: attention-deficit hyperactivity disorder, CanUD: cannabis use disorder, OUD: opioid use disorder, PAU: problematic alcohol use, PTU: problematic tobacco use, CI: confidence interval, SNP: single nucleotide polymorphism. p<0.05*; p<0.001***.
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