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

José Guzmán-Parra ,Fermín Mayoral,Jesus Haro González,Francisco Del Río Noriega,Josef Frank,Markus M Nöthen,Fermín Pérez ,Susana Gil Flores,Sven Cichon,Andreas J Forstner,Jana Strohmaier,Francisco J Cabaleiro Fabeiro,Jerome C Foo,Fabian Streit,Yolanda De Diego-Otero,Berta Moreno‐Küstner ,Franziska Degenhardt,Maria J Gonzalez ,Fabio Rivas,Lea Sirignano,Guillermo Orozco Díaz ,Stephanie H Witt,Stefan Herms,Till F M Andlauer,Stefanie Heilmann‐Heimbach ,Per Hoffmann,Georg Auburger,Marcella Rietschel

doi:10.1038/s41398-020-01146-0

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.

Highlights

Bipolar disorder (BD) is a severe, highly heritable mental disorder characterized by fluctuations in mood state and energy with recurring episodes of depression altering withGuzman-Parra et al Translational Psychiatry (2021)11:31 have a shorter duration, are not characterized by a marked impairment in social or occupational functioning, and do not require hospitalization; the occurrence of any psychotic symptoms qualifies an episode as manic[2].Until recently, it was thought that both BD subtypes could be classified along a spectrum of the affective disorders defined by the extent and severity of mood elevation (i.e., major depressive disorder (MDD) < BD-II < BDI)
Among the variables related to the clinical course of disorder (Table 2), BD type I (BD-I) patients more frequently showed incapacity during depressive episodes (odds ratio (OR) = 2.51, 95% confidence interval (CI) = 1.47-4.28, p = 7.07 × 10−04) after Bonferroni correction for 37 independent tests (α = 1.35 × 10−03; 37 principal components explain 99.3% of the phenotypic variance)
The present study investigated phenotypic and genetic differences between BD-I and BD-II patients of BD multiplex families: First, patients diagnosed with BD-I showed both more severe manic episodes, with frequent inattention and reckless behavior, and more serious depressive episodes, which were often characterized by incapacity

Summary

Introduction

It was thought that both BD subtypes could be classified along a spectrum of the affective disorders defined by the extent and severity of mood elevation (i.e., major depressive disorder (MDD) < BD-II < BDI) This concept is in line with findings of BD-I patients suffering from more psychotic[3,4,5,6] and melancholic symptoms[3], more hospitalizations[6,7,8], and more severe and widespread impairment of cognitive functions[9]. This concept has been challenged by a series of studies which report a higher total number of episodes[12,13,14], increased comorbidity with anxiety disorders[8,13,14] and personality disorders[8,15], as well as lower functioning[15] and quality of life[16] in BD-II compared to BD-I patients, these findings were not consistent across studies[7,8,17,18].

Methods

Results

Conclusion