Association of aetiological factors for hypomanic symptoms, bipolar disorder and other severe mental illnesses: twin and polygenic risk score analysis

Hosang, G.M. and Martin, J. and Karlsson, R. and Lundström, S. and Larsson, H. and Ronald, Angelica and Lichtenstein, P. and Taylor, M.J. (2022) Association of aetiological factors for hypomanic symptoms, bipolar disorder and other severe mental illnesses: twin and polygenic risk score analysis. JAMA Psychiatry 79 (2), pp. 143-150. ISSN 2168-622X.

Abstract

Importance: Subsyndromal hypomanic symptoms are relatively common in the general population and are linked to the onset of bipolar disorder. Little is known about their aetiology and whether this is shared with the aetiology of bipolar disorder or other mental illnesses. Objective: This is the first twin study to examine the genetic and environmental architecture of hypomanic symptoms in a non-clinical youth sample, and compare estimates at varying severity levels and their relationship with diagnosed bipolar disorder. Associations between hypomania and polygenic risk scores [PRS] for bipolar disorder, major depressive disorder and schizophrenia were also investigated. Design, Setting and Participants: This study used phenotypic and genetic data from the Child and Adolescent Twin Study in Sweden. Main Outcomes and Measures: Hypomanic symptoms were assessed using the parent-rated Mood Disorders Questionnaire when the twins were 18. Bipolar disorder diagnosis and/or lithium prescription were ascertained from national registries for residents of Sweden. PRS for psychiatric disorders were calculated using independent discovery genetic data. Results: 8,568 twin pairs aged 18 (54.7% females) were included in the study. The hypomania heritability estimate was 59% (95% Confidence Intervals [CI] 52%-64%) for males and 29% (95% CI 16%-44%) for females. Unique environmental factors accounted for 41% (95% CI 36%-47%) of the hypomania variance in males and 45% (95% CI 40%-50%) in females. Shared environmental factors were only detected for females and explained 26% (95% CI 13%-38%) of the variance. The heritability estimates were fairly consistent across different hypomania severity groups. Moderate genetic (.40, 95% CI .21-.58) and shared environmental (.41, 95% CI .03-.75) correlations between hypomania and diagnosed bipolar disorder were found. Hypomania was significantly associated with the PRS for schizophrenia and major depressive disorder but not bipolar disorder (bipolar I or II). Conclusions and Relevance: Higher heritability for hypomania was found for males compared to females. The results highlight the shared aetiologies between hypomanic symptoms, bipolar disorder, major depression and schizophrenia in youths. Future research should focus on identifying specific shared genetic and environmental factors. These findings support a possible dimensional model of bipolar disorder, with hypomania representing a continuous trait underlying the disorder.

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