Van Der Veen, Tracey; (2025) Genomics Yields Insights into Bipolar Disorder Architectures: Pleiotropic Genes and Polygenic Burdens. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Genome-wide association studies (GWAS) have enhanced the understanding of the genetics of bipolar disorder (BD), yet its profound clinical and genetic heterogeneity remains a major obstacle to diagnosis and treatment. The wide range of clinical presentations, partly driven by high rates of comorbidity and individual variability, can obscure genetic discoveries and complicates the search for reliable biomarkers. Aims: This thesis aims to deconstruct the clinical heterogeneity of BD by identifying novel dimensional frameworks by dissecting the genetic architecture of specific clinical subphenotypes. The central goal is to identify distinct genetic mechanisms and biological pathways that can inform biomarker discovery, advance precision medicine, and identify potentially new functional genomic targets. Methods: This research employed a multi-stage approach, beginning with the development of a dimensional model of BD psychopathology that integrated premorbid factors (Chapter 3). Subsequent analyses utilized large-scale genetic data to assess transdiagnostic risk from schizophrenia (Chapter 4), delineate the genetic architecture of 11 distinct clinical subphenotypes using Multi-Trait Analysis of GWAS (MTAG) (Chapter 5), and evaluate the impact of ascertainment and ancestry on polygenic prediction (Chapter 6). Results: A novel ‘Adverse Chronic Trajectory’ (ACT) dimension was identified, potentially linking premorbid neurodevelopmental deficits to chronic BD outcomes; this dimension was genetically associated with polygenic risk for ADHD and anxiety, not core BD. Multi-trait analyses of eleven subphenotypes revealed four underlying genetic dimensions, including a ‘Severe Illness’ dimension defined by a unique neuro-immune signature (a protective association with the human Major Histocompatibility Complex (MHC) Human Leukocyte Antigen, Class II, DM Alpha gene (HLA-DMA) and specific risk loci Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A), and a ‘Comorbidity’ dimension linked to neurodevelopmental genes such as Deleted in Colorectal Carcinoma (DCC). Further analyses demonstrated that the predictive power of polygenic scores is substantially influenced by both patient ascertainment strategies and genetic ancestry. Conclusions: This thesis advances the understanding of BD’s genetic architecture by providing a biological framework that helps explain its clinical diversity. The identification of distinct genetic dimensions and subphenotype-specific pathways begins to address the “hidden heritability” challenge by revealing previously obscured genetic mechanisms. These findings offer novel, biologically grounded hypotheses for future research and lay the groundwork for developing stratified, personalized treatment strategies in the pursuit of precision psychiatry.

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