Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families

Abstract

The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.

Fig. 1. Polygenic risk score analyses in a subset of 156 family members.

A BD-II patients showed a significantly higher MDD PRS than BD-I cases. SD standard deviation. Results from a logistic mixed regression model using PRS as predictors, BD type as the outcome, and sex and age as covariates (for full results see Supplementary Table S5). Comparisons significant after Bonferroni correction for three tests (α = 0.05/3 = 0.0167) are marked with an asterisk. For the SCZ PRS, the one-sided hypothesis was that BD-I cases have higher PRS; for the MDD PRS, the one-sided hypothesis was that BD-II cases show higher PRS. B Analysis of dichotomous clinical course and symptom variables with p < 5.56 × 10⁻⁰³ in the phenotypic analyses (see Tables 2–3). Results from a logistic mixed regression model using PRS as predictors, symptoms as the outcome, and sex and age as covariates (for full results see Supplementary Table S6). Bonferroni-corrected threshold for significance: α = 0.05/(6 × 3) = 2.78 × 10⁻⁰³. For all PRS, the one-sided hypothesis was that the symptom severity increases with the PRS. PRS polygenic risk score, BD bipolar disorder, MDD major depressive disorder, SCZ schizophrenia, 95% CI 95% confidence interval, depr. epis. depressive episodes.