YOUTH AT RISK OF BIPOLAR DISORDER: TRACKING TRAJECTORIES, OUTCOMES AND BIOMARKERS USING NEUROIMAGING, GENOMICS AND EPIGENOMICS

Abstract

Longitudinal prospective studies in high-risk populations are key for identifying pre-morbid risk factors for the development of psychopathology. The Australia-US collaborative Bipolar high-risk study comprises 3 groups of participants aged 12-30 years: ‘high-risk’ (with a sibling or parent with bipolar-I or -II), controls with no family history, and an unrelated group of BD-probands; with clinical, demographic and biological data. Familial risk is sometimes considered a surrogate for genetic risk (that is indexed via inherited DNA variants), but we know that this is a simplification of the ‘heritable’ component, which might comprise both direct and indirect genetic effects as well as the impact of family environment. We have used multiple analytic approaches to define and characterize features of disease risk, using neuroimaging, genomics and epigenomics. Analysis of magnetic resonance imaging (MRI) data from 217 unrelated Australian ‘Bipolar Kids and Sibs study’ participants (baseline n=217, follow-up n=152) finds accelerated cortical thinning over time (two scans, 2 years apart) in high-risk subjects (n=105) compared to controls (n=112), suggesting an early brain over-growth followed by normalisation towards the typical age of BD onset. Accelerated thickness and volume reductions over time were observed in ‘high-risk’ individuals across multiple cortical regions, relative to controls, including right lateral orbitofrontal thickness (β=.033, p < .001) and inferior frontal volume (β=.021, p < .001). We also find that bipolar polygenic risk (PsychArray) interacts with stress to increase suicide risk. We examined polygenic risk for both suicide attempt and risky behaviour on structural variance in cortical parcellations that have previously shown replicable associations with suicide attempts, finding that structural differences in the anterior cingulate, parahippocampal, and cuneus warrant further investigation as potential biomarkers for suicide attempts, particularly within the context of BD. Examination of epigenetic markers (450k/EPIC array) shows that genome-wide methylation patterns are broadly impacted by polygenic risk; highlighting an important interplay between genomically inherited risk and the potential biological encoding of environmental exposures. We are now collecting a 3rd MRI scan to capture nonlinear cortical developmental trajectories, and a 2nd blood sample to extend our baseline epigenetic work, derive serum measures and examine mRNA transcription patterns as potential biomarkers of emergent psychopathology. Brain regions associated with both genetic and clinical measures of psychopathology may serve as viable biomarkers, with clinical utility for the identification of individuals who are at greatest risk of developing psychopathology or suicidal intent. Future work will enable integration of these features into a prediction model of disease, to identify biological subgroups on the trajectory towards mental illness.