Association of polygenic risk for bipolar disorder with grey matter structure and white matter integrity in youth

Abstract

There is a gap in knowledge regarding the polygenic underpinnings of brain anomalies observed in youth bipolar disorder (BD). This study examined the association of a polygenic risk score for BD (BD-PRS) with grey matter structure and white matter integrity in youth with and without BD. 113 participants were included in the analyses, including 78 participants with both T1-weighted and diffusion-weighted MRI images, 32 participants with T1-weighted images only, and 3 participants with diffusion-weighted images only. BD-PRS was calculated using PRS-CS-auto and was based on independent adult genome-wide summary statistics. Vertex- and voxel-wise analyses examined the associations of BD-PRS with grey matter metrics (cortical volume [CV], cortical surface area [CSA], cortical thickness [CTh]) and fractional anisotropy [FA] in the combined sample, and separately in BD and HC. In the combined sample of participants with T1-weighted images (n = 110, 66 BD, 44 HC), higher BD-PRS was associated with smaller grey matter metrics in frontal and temporal regions. In within-group analyses, higher BD-PRS was associated with lower CTh of frontal, temporal, and fusiform gyrus in BD, and with lower CV and CSA of superior frontal gyrus in HC. In the combined sample of participants with diffusion-weighted images (n = 81, 49 BD, 32 HC), higher BD-PRS was associated with lower FA in widespread white matter regions. In summary, BD-PRS calculated based on adult genetic data was negatively associated with grey matter structure and FA in youth in regions implicated in BD, which may suggest neuroimaging markers of vulnerability to BD. Future longitudinal studies are needed to examine whether BD-PRS predicts neurodevelopmental changes in BD vs. HC and its interaction with course of illness and long-term medication use.

Polygenic Risk Scores for Bipolar Disorder: Progress and Perspectives

“…The results showed that BD-PRS is negatively correlated with gray matter structure and fractional anisotropy (FA) in regions associated with BD in adolescents. 30 These research findings support the feasibility of BD-PRS as a neuroimaging marker for BD. Future longitudinal studies are needed to examine whether BD-PRS can predict neurodevelopmental changes between BD and healthy controls (HC), as well as its interaction with the course of illness and long-term medication use.…”

White and gray matter alterations in bipolar I and bipolar II disorder subtypes compared with healthy controls – exploring associations with disease course and polygenic risk

“…The debate surrounds the suitability of genome-wide PRS as a genetic tool for investigating psychiatric disorders [ 93 ]. While it enhances generalizability by capturing a broad range of common genetic factors for BD [ 55 ], its inclusion of alleles with potentially diverse associations with brain structure may mask effects of specific gene sets [ 93 ]. This debate is reflected in conflicting findings: On the one hand, there are studies failing to establish significant associations between BD or SZ PRS and brain structure [ 35 , 93 ].…”

“…This debate is reflected in conflicting findings: On the one hand, there are studies failing to establish significant associations between BD or SZ PRS and brain structure [ 35 , 93 ]. In contrast, a recent study in bipolar adolescents, benefiting from fewer confounding factors such as illness course or medication, demonstrated higher bipolar PRS scores correlating with both GM structure and WM diffusion [ 55 ].…”

“…A higher genetic load, which was also related to a more severe course of BD across subtypes [ 52 ], could also be linked to brain structural alterations [ 53 – 55 ]. Despite evidence for subtype-specific neuroanatomy and genetics, the relationship between these features in BD subtypes remains uninvestigated.…”