Heritability, phenotypic, and genetic correlations across dimensional and categorical models of bipolar disorder in a family sample

Alejandro Arbona-Lampaya; Heejong Sung; Alexander D'Amico; Emma E M Knowles; Emily K Besançon; Ally Freifeld; Ley Lacbawan; Fabiana Lopes; Layla Kassem; Antonio E Nardi; Francis J McMahon

doi:10.1016/j.jad.2024.12.030

Heritability, phenotypic, and genetic correlations across dimensional and categorical models of bipolar disorder in a family sample

J Affect Disord. 2024 Dec 10:372:394-401. doi: 10.1016/j.jad.2024.12.030. Online ahead of print.

Affiliations

¹ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; School of Medicine, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico. Electronic address: alejandro.arbona@upr.edu.
² Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
³ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
⁵ Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. Electronic address: mcmahonf@mail.nih.gov.

PMID: 39667704
DOI: 10.1016/j.jad.2024.12.030

Abstract

Background: Bipolar disorder (BD) presents with a wide range of symptoms that vary among relatives, casting doubt on categorical illness models. To address this uncertainty, we investigated the heritability and genetic relationships between categorical and dimensional models of BD in a family sample.

Methods: This retrospective study included participants (n = 397 Females, n = 329 Males, mean age 47 yr) in the Amish-Mennonite Bipolar Genetics (AMBiGen) study from North and South America that were assigned categorical mood disorder diagnoses ("narrow" or "broad") by structured psychiatric interview and completed the Mood Disorder Questionnaire (MDQ), which assesses lifetime history of manic symptoms and associated impairment. MDQ-dimensions were analyzed by Principal Component Analysis (PCA). Heritability and genetic overlaps between categorical diagnoses and MDQ-dimensions were estimated with SOLAR-ECLIPSE within 432 genotyped participants.

Results: Individuals diagnosed with BD (n = 124) endorsed more MDQ items (61 %) than those with other mood disorders (26 %) or with no mood disorder (9 %), as expected. PCA suggested a three-component model for the MDQ, capturing 60 % of the variance. Heritability of the MDQ and its principal components was significant but modest (20-30 %, p < 0.001). Genetic correlations between MDQ measures and categorical diagnoses (ρG = 0.62-1.0; p < 0.001) were stronger than phenotypic correlations (ρP = 0.11-0.58; p < 0.001).

Limitations: Recruitment through probands with BD resulted in increased prevalence of BD in this sample, limiting generalizability. Unavailable genetic data reduced sample size for some analyses.

Conclusion: Findings support a genetic continuity between dimensional and categorical models of BD and suggest that the MDQ is a useful phenotype measure for genetic studies of BD.

Keywords: Bipolar Disorder; Genetic correlation; Heritability; Mood Disorder Questionnaire; Mood disorders; Principal Component Analysis.