Neurocognitive correlates of polygenic risk for bipolar disorder among youth with and without bipolar disorder

Introduction: There is well-established evidence of reduced neurocognitive performance in adults and youth with bipolar disorder (BD). However, little is known about the polygenic underpinnings of neurocognition in individuals with BD, particularly in youth. The current study aimed to examine the association between polygenic risk score for BD (BD-PRS) and neurocognition among youth with BD and healthy controls (HC).

Methods: 129 youth of European ancestry (72 BD, 57 HC), ages 13-20 years, were included. Six neurocognitive tasks within the Cambridge Neuropsychological Test Automated Battery were assessed. General linear models were used to examine the association between BD-PRS and neurocognitive composite scores, controlling for age, sex, IQ, and two genetic principal components.

Results: In the overall sample, higher BD-PRS was associated with significantly poorer affective processing (β = -0.25, p = 0.01), decision-making (β = -0.23, p = 0.02), and sustained attention (β = -0.28, p = 0.002). Secondary analyses revealed that higher BD-PRS was associated with significantly poorer sustained attention within the BD group (β = -0.27, p = 0.04), and with significantly poorer affective processing within the HC group (β = -0.29, p = 0.04).

Limitations: Cross-sectional design. Modest sample size may have reduced power to detect smaller effect sizes.

Conclusion: The current study found that higher BD-PRS generated based on adult GWAS was associated with poorer neurocognitive performance in youth with BD and HC. Future longitudinal studies incorporating repeated neurocognitive assessments would further inform whether the associations of BD-PRS with neurocognition vary from youth to adulthood, and whether BD-PRS is associated with differential neurodevelopmental trajectories in individuals with and without BD.