The causes of clinical variability in bipolar disorder (BD) must be understood to guide investigations of underlying processes and innovative stratification techniques. For a study, researchers sought to determine the genetic risk factors that BD, schizophrenia, and major depressive disorder (MDD) all share and those that set each condition apart from the others, as well as to look at links between each factor and the heterogeneity of important BD symptoms.

By using data from the Bipolar Disorder Research Network in the UK, genomic structural equation modeling was used to analyze genome-wide association studies of schizophrenia, BD, and MDD. In an independent BD data set, each component’s polygenic risk scores (PRS) were examined for associations with symptoms. Adults with DSM-IV BD or bipolar-type schizoaffective disorder were included. Data were gathered between January 2000 and December 2013, and data were examined between June 2020 and February 2022. The Bipolar Affective Disorder Dimensional Scale was used to assess patients with BD for mania, depression, psychosis, and mood incongruence of psychosis. PRS reflecting the components of liability were examined for associations with these symptoms.

The mean (SD) age of the 4,429 individuals that were included was 46.2 (12.3) years, with 3,012 (68.0%) of them being female. Mania and psychosis were connected to the shared liability component (mania β = 0.29; 95% CI, 0.23-0.34; P = 3.04 × 10-25; psychosis β = 0.05; 95% CI, 0.04-0.07; P = 2.33 × 10-13) and the components that separate schizophrenia from BD (mania β = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis β = 0.03; 95% CI, 0.01-0.04; P = 1.0 × 10-4) and BD (mania β = 0.14; 95% CI, 0.09-0.20; P = 1.99 × 10-7; psychosis β = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD distinguishing component was not linked with psychosis irrespective of mania but was associated with mania regardless of effects on psychosis (β = 0.14; 95% CI, 0.08-0.20; P = 4.32 × 10-6). On the other hand, the schizophrenia distinguishing component was not related to mania independently of psychosis, but rather with psychosis regardless of effects on mania(β = 0.01; 95% CI, 0.003-0.03; P = .02). Only the schizophrenia distinguishing component was linked to the mood incongruence of psychosis (β = 0.03; 95% CI, 0.01-0.05; P = .005). Depression had a lower BD distinguishing component (β = 0.07; 95% CI, 0.01-0.12; P = .01) but a greater MDD differentiating component (β = −0.11; 95% CI, −0.17 to −0.06; P = 7.06 × 10-5).

Clinical heterogeneity in the study of BD represented the burden of liability to BD and the contribution of alleles that differ in their effects on risk for other ,disorders; mania, psychosis, and depression were related to the genetic liability components that differentiated BD, MDD, and schizophrenia, respectively. In order to categorize patients, create precision treatments, and uncover the many pathophysiological mechanisms causing BD, it will be imperative to comprehend the underlying causes of this etiological heterogeneity.