Association of polygenic risk for cannabis use disorder with brain structure among youth with and without bipolar disorder.

Abstract

Background: Cannabis use disorder (CUD) is common in youth, with elevated rates among youth with bipolar disorder (BD). Cannabis use among youth is also associated with anomalous neurostructural phenotypes. While neurophysiological mechanisms associated with cannabis use may contribute to these differences, genetic predisposition to CUD may also be contributory. Given the lack of prior studies on this topic, we examined polygenic risk scores for CUD (CUD-PRS) in relation to brain structure among youth with and without BD.

Methods: T₁-weighted magnetic resonance imaging (MRI) was collected for 114 participants ages 13-20 (n = 67 BD, n = 47 healthy controls (HC)). CUD-PRS was calculated using PRS-CS-auto, based on summary statistics from a genome-wide association study conducted in adults. Covariate-adjusted vertex-wise analyses examined the association of CUD-PRS with cortical volume, surface area (SA), and thickness in the whole sample, and within BD and HC.

Results: In the whole sample, higher CUD-PRS was associated with significantly lower volume and SA in the right superior frontal gyrus (β = -0.31, p < 0.01; β = -0.33, p < 0.01), and with significantly lower SA in the left paracentral lobule (β = -0.37, p = 0.0002). Within HC, higher CUD-PRS was associated with significantly lower volume and SA in the left and right superior frontal gyrus (β = -0.78, p < 0.002; β = -0.66, p < 0.028; β = -0.79, p < 0.0001; β = -0.68, p < 0.0001). There were no significant within-BD results.

Conclusion: Present findings demonstrate a consistent pattern of higher CUD-PRS corresponding with lower regional brain structure, even in the absence of CUD. Future studies are needed to understand the mechanisms, developmental trajectories, and diagnosis-related differences in the observed findings.