Date of Award

January 2026

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Shuangge Ma

Second Advisor

Bao-Zhu Yang

Abstract

Major depressive disorder (MDD) and cardiovascular disease are highly comorbid, yet the extent and biological basis of their shared genetic architecture remains poorly understood. To address this gap, we performed an integrative genomic analysis of 419,403 individuals of European ancestry from the UK Biobank to systematically examine the genetic overlap between MDD and five cardiovascular traits: heart failure (HF), hypertension (HTN), ischemic heart disease (IHD), abnormal heart rhythms (AHR), and cerebrovascular disease (CeVD). Using a multi-layered analytic framework encompassing LD score regression, cross-trait MiXeR, Bayesian colocalization, transcriptome-wide association studies (TWAS), bidirectional Mendelian randomization (MR), and FOCUS fine-mapping, we delineated both the magnitude and biological context of shared genetic liability. We observed a gradient pattern of genetic overlap, with the strongest sharing between MDD and HF (rg = 0.57, 3,000 shared causal variants), and the weakest between MDD and AHR (rg = 0.33, 500 shared causal variants), which was largely driven by non-coding regulatory signals. Colocalization analyses identified 18 shared loci, including APOE (MDD–IHD) and TOMM40 (MDD–CeVD), and TAPBP and MYO1H (MDD–HF), implicating lipid metabolism and mitochondrial dysfunction, along with immune and cytoskeletal processes, as convergent mechanisms underlying psychiatric-cardiovascular comorbidity. TWAS further revealed cross-trait transcriptomic convergence in brain regions relevant to stress regulation, including frontal cortex and hippocampus for MDD–HTN and cerebellar enrichment for MDD–IHD, suggesting neurobiological pathways linking affective dysregulation to cardiovascular risk. Causal inference using MR established a directional effect of MDD on cardiovascular outcomes, conferring increased risk for HTN (61%), IHD (45%), HF (24%), and CeVD (15%), whereas reverse causal effects were minimal, with only a modest contribution of AHR to MDD risk (6%). Fine-mapping prioritized FAM89A (MDD–HTN) and TMEM106B (MDD–IHD) as high-confidence shared genes, supported by convergent evidence across GWAS, TWAS, and probabilistic fine-mapping. These findings provide a comprehensive map of the shared genetic architecture between depression and cardiovascular disease, identify specific genes and pathways for functional investigation, and support integrated prevention strategies targeting both psychiatric and cardiovascular health. This study provides convergent genetic, transcriptomic, and causal evidence that MDD is not only comorbid with cardiovascular diseases but contributes to its biological risk architecture. The identification of overlapping loci, relevant brain–cardiovascular pathways, and directional effects supports a model linking psychiatric and cardiovascular conditions through common biological mechanisms. From a translational perspective, these results prioritize specific genes and pathways for functional validation, suggest that depression may serve as an early indicator of cardiovascular risk, and motivate prevention and intervention strategies that jointly target mental and cardiovascular health.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 09/16/2027

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