Neurostructural Correlates of Polygenic Risk for Coronary Artery Disease in Relation to Youth Bipolar Disorder

Bipolar disorder (BD), characterized by anomalous neurostructural phenotypes, is also strongly associated with cardiovascular disease. Here we examined polygenic risk for coronary artery disease (CAD) in relation to gray matter structure in youth BD.

Youth participants (mean age 17.1 years; n = 66 BD, n = 45 healthy controls [HC]) underwent T1-weighted magnetic resonance imaging. CAD polygenic risk scores (CAD-PRS) were calculated using independent, adult genome-wide summary statistics. Covariate-adjusted vertex-wise analyses examined the association of CAD-PRS with cortical volume, thickness, and surface area (SA) in the overall sample, and within BD and HC groups. Additional region-of-interest (ROI) analyses were conducted to examine the anterior cingulate cortex (ACC), amygdala, and hippocampus. Exploratory sex-stratified analyses were also undertaken.

In the overall sample, higher CAD-PRS was associated with lower right inferior temporal gyrus volume (β = -0.32, p = 0.03). There were also negative associations between CAD-PRS and brain structure within BD (5 cortical thickness clusters) and HC (1 SA cluster). Within the BD group, sex-stratified analyses revealed significant findings for females, but not for males. ROI analyses revealed a nominal association of higher CAD-PRS with lower ACC thickness in the BD group (β = -0.31, p_uncorrected = 0.05, p_corrected = 0.20).

Higher CAD-PRS was associated with lower regional gray matter structure in youth, in regions implicated in BD. Findings were more pronounced in the BD group, particularly among females, and related to cortical thickness specifically. Future longitudinal studies are needed to examine the association of CAD-PRS with neurodevelopmental changes over time and to discern mechanisms underlying the observed findings.