Investigating Shared Cardiovascular Factors and Genetic Overlap of Pregnancy-Related Disorders, Major Depressive Disorder, and Alzheimer’s Disease

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BACKGROUND: Pregnancy-related disorders, such as hypertensive disorders of pregnancy (HDPs) and postpartum depression, have consequences for maternal health, increasing risk for major depressive disorder (MDD) and Alzheimer's disease (AD). Observational studies show intertwined pathophysiologies and shared cardiovascular factors. However, genetic links of cardiovascular factors with pregnancy-related disorders, MDD, and AD, as well as the genetic mechanisms between the disorders, have not been fully established. METHODS: Using summary statistics from female-specific genome-wide association studies, we estimated genetic correlations and causal associations, using Mendelian randomization, between cardiovascular factors (C-reactive protein, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglycerides), pregnancy-related disorders (HDPs and postpartum depression), MDD, and AD. For significant associations, body mass index (BMI), as a known confounder, was included in multivariable Mendelian randomization analyses. Furthermore, we applied causal mixture models (MiXeR) to explore polygenic overlap between pregnancy-related disorders, MDD, and BMI. RESULTS: We found widespread genetic correlations between cardiovascular factors, pregnancy-related disorders, and MDD. Using Mendelian randomization, higher triglycerides and lower HDL cholesterol were causally linked to higher HDP risk, and higher LDL cholesterol was linked to higher AD risk. When BMI was included, only the effect of triglycerides on HDP remained significant. Trivariate MiXeR estimated substantial polygenic overlap of pregnancy-related disorders with MDD and BMI. CONCLUSIONS: Using multiple genetic approaches, our findings indicate some shared cardiovascular factors associated with pregnancy-related disorders, MDD, and AD, partially driven by BMI. BMI should be further explored as a modifiable factor genetically linked to pregnancy-related, mental, and brain disorders. Our findings highlight the relevance of early prevention of genetically interconnected disorders across the female lifespan.

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