Polygenic Risk Scores and Intermediate Phenotypes in Youth Bipolar Disorder

Abstract

Bipolar disorder (BD) is a polygenic condition with a heritability of up to 85%. Polygenic risk score(s) (PRS), calculated as the weighted sum of single nucleotide polymorphism risk alleles identified by genome-wide association studies, can be studied as an index of an individual’s genetic liability for BD. Recent studies have found that PRS for BD (BD-PRS) is elevated in adults with BD and youth at familial risk for BD. There is also well-established evidence of neuroimaging and neurocognitive anomalies in youth with BD. Nonetheless, there is ongoing conjecture regarding the validity of BD in youth. One approach to validate youth BD is to demonstrate that it has similar genetic underpinnings as adult BD. This thesis therefore focuses, for the first time, on the polygenic underpinning of BD diagnosis and related intermediate phenotypes in youth with BD. Participants were youth of European ancestry, aged between 13-20 years. DNA was extracted from saliva and genotyped. PRS, based on independent adult genome-wide association summary statistics, were constructed using PRS-CS-auto. Clinical diagnoses were determined by semi-structured interviews. Brain images were collected using 3-Tesla magnetic resonance imaging. Neurocognition was examined using a computerized automated test battery. BD-PRS was significantly higher in youth with BD than controls, with youth at high risk for BD numerically intermediate. Higher BD-PRS was associated with smaller grey matter structure in frontal and temporal regions, poorer white matter integrity in projection tracts, altered resting-state functional connectivity of salience, frontoparietal, and visual network, and poorer neurocognitive performance on sustained attention, decision-making, and affective processing. In conclusion, the alignment of present youth BD findings with prior adult BD findings adds to the biological validation of BD in youth. This may help reduce doubt and stigma. This cross-sectional research will inform future longitudinal studies, which are needed to elucidate the mechanistic effects of BD-PRS on BD diagnosis and related intermediate phenotypes. Ultimately, continued progress on this line of research has the potential to inform clinical decisions related to early detection, diagnostic classification, risk prediction, and treatment of youth BD.