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HIGHER POLYGENIC RISK FOR MITOCHONDRIAL DYSFUNCTION IS ASSOCIATED WITH LOWER CEREBRAL BLOOD FLOW IN YOUTH WITH BIPOLAR DISORDER

Nidhi Kulkarni — Clement Zai2, Kody Kennedy1, Megan Mio1, Ana Andreazza2, Vanessa Goncalves2, L. Trevor Young2, Bradley MacIntosh3, Benjamin Goldstein4 1Centre for Youth Bipolar Disorder, CAMH, 2CAMH; University of Toronto, 3Oslo University Hospital; Sunnybrook Research Institute; University of Toronto, 4Centre for Youth Bipolar Disorder, CAMH; University of Toronto

2026 ASCP Annual Meeting

Introduction

Bipolar disorder (BD) is a polygenic disease characterized by mitochondrial dysfunction and anomalous cerebral blood flow (CBF), which are interconnected. We examined the association of polygenic risk scores for mitochondrial dysfunction (Mito-PRS) with CBF in relation to youth BD.

Methods

100 participants (17.2±1.6 years old; n=61 BD, n=39 controls) underwent arterial spin labelling magnetic resonance imaging to quantify CBF. Mito-PRS were calculated using adult genome-wide association study summary statistics for BD, extracting variants related to mitochondrial function only. Covariate-adjusted analyses examined the association of Mito-PRS with CBF in global grey matter, and in anterior cingulate cortex and amygdala regions of interest. Sex-stratified analyses and PRS-by-diagnosis interaction effects were also examined. Sensitivity analyses controlled for psychotropic medications, traditional cardiovascular risk factors, mood, and 10 genetic principal components.

Results

Higher Mito-PRS was associated with lower global grey matter CBF in the overall sample (β=-0.29, p=0.003) and within BD (β=-0.36, p=0.006). These findings were significant in females but not males. When controlling for medications and cardiovascular risk factors, most findings remained significant and additional findings emerged. Mito-PRS associations with regions of interest were not significant in primary analyses, but were significant when controlling for cardiovascular risk factors, mood, and 10 principal components.

Conclusion

In a sample of youth with BD, higher polygenic risk for mitochondrial dysfunction was associated with lower global CBF, particularly in females. Controlling for cardiovascular risk factors strengthened study findings. Future studies powered to evaluate cardiovascular riskrelated effects, mood-related effects, and putative mediators of the observed findings are warranted.