Measuring the associations between brain morphometry and polygenic risk scores for substance use disorders in drug-naive adolescents.

Substance use has been associated with differences in adult brain morphology; however, it is unclear whether these differences precede or are a result of substance use substance use. We investigated the impact of polygenic risk scores (PRSs) for cannabis use disorder (CUD) and general substance use and substance use disorder liability (SU/SUD) on brain morphology in drug-naïve adolescents. Baseline data were used from 1,874 European-descent participants (ages 9-11) comprising 222, 328 and 387 pairs of MZ twins, DZ twins, and Non-Twin Siblings, respectively, in the Adolescent Brain Cognitive Development Study. We fitted multivariate twin models to estimate the putative effects of CUD, SU/SUD, and brain region-specific PRSs. These models assessed their influence on six subcortical and two cortical phenotypes. PRS for CUD and SU/SUD were created based on GWAS conducted by Johnson et al. (2020) and Hatoum et al. (2023), respectively. When decomposing variance in each brain region of interest (ROI), we used the corresponding ROI-specific PRS. Brain morphometry in drug-naive subjects was unrelated to CUD PRS. The variance explained in each ROI by its corresponding PRS ranged from 0.8-4.4%. The SU/SUD PRS showed marginally significant effects (0.2-0.4%) on cortical surface area and nucleus accumbens volume, but overall effect sizes were small. Our findings indicate that differences in brain morphometry among baseline drug-naive individuals are not associated with the genetic risk for CUD but show a weak association with general addiction and substance use risk (SU/SUD), particularly in nucleus accumbens volume and total cortical surface area.