Stratification of bipolar disorder: harnessing clinical heterogeneity and genetics shared with other disorders (360G-Wellcome-209176_Z_17_Z)

The bipolar disorder diagnostic category, while clinically useful lacks biological precision/validity. There is consensus that this biological imprecision is impeding aetiological research and the development of new therapeutic interventions. BD overlaps with schizophrenia (SCZ) and Major depressive disorder (MDD) in its clinical presentation. It has a large polygenic component to it genetic aetiology which it partially shared with SCZ and MDD. This suggests the hypothesis that the clinical heterogeneity seen in BD may be due to underlying causal heterogeneity and the degree of clinical similarity between individuals diagnosed with BD, SCZ and MDD reflects overlapping risk alleles which selectively influence specific, shared clinical characteristics, rather than the global risk for the disorders. This study will use genome-wide and pathway-specific polygenic risk score methods to identify biologically valid stratifiers for BD, informed by psychopathological characteristics AND genetic liability. BD may be the extreme phenotypic expression of psychopathological dimensions distributed throughout the general population to explore this further, generalised latent variable modelling will be used to examine and compare the latent structure of the psychopathological phenotypes in BD cases with those found in the general population and LD score regression will test for genetic correlation