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

Hannah Oppenheimer; Alexey Shadrin; Jonas Ø Andersen; Louise S Schindler; Arielle Crestol; Ole A Andreassen; Lars T Westlye; Ann-Marie G de Lange; Dennis van der Meer; Claudia Barth

doi:10.1016/j.biopsych.2025.09.018

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

Biol Psychiatry. 2025 Oct 9:S0006-3223(25)01519-7. doi: 10.1016/j.biopsych.2025.09.018. Online ahead of print.

Affiliations

¹ Division for Mental Health and Substance Abuse, Diakonhjemmet Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Norway. Electronic address: hannah.oppenheimer@psykologi.uio.no.
² Center for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Division for Mental Health and Substance Abuse, Diakonhjemmet Hospital, Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Department of Psychiatry, University of Oxford, Oxford UK.
⁵ Center for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; KG Jebsen Center for Neurodevelopmental Disorders, University of Oslo & Oslo University Hospital, Oslo, Norway.
⁶ Department of Psychology, University of Oslo, Norway; Center for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; KG Jebsen Center for Neurodevelopmental Disorders, University of Oslo & Oslo University Hospital, Oslo, Norway.
⁷ Department of Psychology, University of Oslo, Norway; Department of Psychiatry, University of Oxford, Oxford UK.
⁸ Division for Mental Health and Substance Abuse, Diakonhjemmet Hospital, Oslo, Norway; Department of Psychiatry and Neuroscience (CCM), Charité - Universitätsmedizin Berlin, Berlin, Germany; Research Unit Gender in Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: claudia.barth@charite.de.

PMID: 41075965
DOI: 10.1016/j.biopsych.2025.09.018

Abstract

Background: Pregnancy-related disorders, such as hypertensive disorders of pregnancy (HDP) 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, HDL-cholesterol, LDL-cholesterol, and triglycerides), pregnancy-related disorders (HDP and postpartum depression), MDD, and AD. For significant associations, BMI, as a known confounder, was included in multivariable Mendelian randomization analyses. Further, 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 to higher AD risk. When including BMI, 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, partly 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.

Keywords: Alzheimer’s disease; cardiovascular factors; female health; genetic overlap; major depressive disorder; pregnancy-related disorders.