Genetic Liabilities Differentiating Bipolar Disorder, Schizophrenia, and Major Depressive Disorder, and Phenotypic Heterogeneity in Bipolar Disorder

IMPORTANCE Understanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms. OBJECTIVE To identify components of genetic liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component. DESIGN, SETTING, AND PARTICIPANTS Using data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with DSM-IV BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022. MAIN OUTCOMES AND MEASURES PRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale. RESULTS Of 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania beta = 0.29; 95% CI, 0.23-0.34; P = 3.04 x 10(-25); psychosis beta = 0.05; 95% CI, 0.04-0.07; P = 2.33 x 10(-13)) and the components that differentiate each of schizophrenia (mania beta = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis beta = 0.03; 95% CI, 0.01-0.04; P = 1.0 x 10(-4)) and BD (mania beta = 0.14; 95% CI, 0.09-0.20; P = 1.99 x 10(-7); psychosis beta = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (beta = 0.14; 95% CI, 0.08-0.20; P = 4.32 x 10(-)(6)) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (beta = 0.01; 95% CI, 0.003-0.03; P = .02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (beta = 0.03; 95% CI, 0.01-0.05; P = .005). Depression was associated with higher MDD differentiating component (beta = 0.07; 95% CI, 0.01-0.12; P = .01) but lower BD differentiating component (beta = -0.11; 95% CI, -0.17 to -0.06; P = 7.06 x 10(-5)). CONCLUSIONS AND RELEVANCE In this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.