TY - JOUR
T1 - Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders
AU - Koller, Dora
AU - Mitjans, Marina
AU - Kouakou, Manuela
AU - Friligkou, Eleni
AU - Cabrera-Mendoza, Brenda
AU - Deak, Joseph D.
AU - Llonga, Natalia
AU - Pathak, Gita A.
AU - Stiltner, Brendan
AU - Løkhammer, Solveig
AU - Levey, Daniel F.
AU - Zhou, Hang
AU - Hatoum, Alexander S.
AU - Kember, Rachel L.
AU - Kranzler, Henry R.
AU - Stein, Murray B.
AU - Corominas, Roser
AU - Demontis, Ditte
AU - Artigas, María Soler
AU - Ramos-Quiroga, Josep Antoni
AU - Gelernter, Joel
AU - Ribasés, Marta
AU - Cormand, Bru
AU - Polimanti, Renato
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
KW - Attention-deficit hyperactivity disorder
KW - Mendelian randomization
KW - Pleiotropy
KW - Polygenic risk scoring
KW - Substance use disorders
UR - http://www.scopus.com/inward/record.url?scp=85184594139&partnerID=8YFLogxK
U2 - 10.1016/j.psychres.2024.115758
DO - 10.1016/j.psychres.2024.115758
M3 - Journal article
C2 - 38335780
AN - SCOPUS:85184594139
SN - 0165-1781
VL - 333
JO - Psychiatry Research
JF - Psychiatry Research
M1 - 115758
ER -