# Measuring the Associations Between Brain Morphometry and Polygenic Risk Scores for Substance use Disorders in Drug-Naive Adolescents

## TL;DR

This study examines whether genetic risk for substance use disorders is linked to brain structure in drug-naive adolescents.

## Contribution

It is the first to explore polygenic risk score associations with brain morphometry in drug-naive adolescents.

## Key findings

- Genetic risk for cannabis use disorder showed no association with brain morphometry in drug-naive adolescents.
- A weak link was found between general substance use disorder risk and brain structure, particularly in the nucleus accumbens and cortical surface area.
- Overall, the associations were small, and the study failed to reject the null hypothesis of no connection between genetic risk and brain structure.

## Abstract

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 1874 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. (Lancet Psychiatry 7:1032, 2020) and Hatoum et al. (Nat Ment Health 1:210–223, 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 to 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. This study failed to reject the null hypothesis of no association between genetic risk for substance use and brain morphometry among baseline drug-naive adolescents. Genetic risk for CUD was not associated with brain morphometry among drug-naive adolescents, but a weak association with general addiction and substance use risk (SU/SUD) particularly in nucleus accumbens volume and total cortical surface area, was observed.

The online version contains supplementary material available at 10.1007/s10519-025-10227-z.