Large-scale blood pressure GWAS accounting for gene-depression interactions in 564,680 individuals from diverse populations

Songmi Lee, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA; Human Genetics Center, Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
Clint L. Miller, Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
Amy R. Bentley, Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Michael R. Brown, Human Genetics Center, Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
Pavithra Nagarajan, Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Raymond Noordam, Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
John L. Morrison, Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
Karen Schwander, Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
Kenneth Westerman, Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Minjung Kho, Graduate School of Data Science, Seoul National University, Seoul, South Korea.
Aldi T. Kraja, University of Mississippi Medical Center, Jackson, MS, USA.
Paul S. de Vries, Human Genetics Center, Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
Farah Ammous, Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
Hughes Aschard, Department of Computational Biology, France Institut Pasteur, Université Paris Cité, 75015 Paris, France.
Traci M. Bartz, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
Anh Do, Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA.
Charles T. Dupont, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
Mary F. Feitosa, Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
Valborg Gudmundsdottir, Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, Department of Health Sciences, University of Iceland, Reykjavik, Iceland.
Xiuqing Guo, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Sarah E. Harris, Lothian Birth Cohorts, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
Keiko Hikino, Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
Zhijie Huang, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
Christophe Lefevre, Department of Data Sciences, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
Leo-Pekka Lyytikäinen, Finnish Cardiovascular Research Center - Tampere, Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Yuri Milaneschi, Department of Psychiatry, Amsterdam UMC/Vrije Universiteit, Amsterdam, the Netherlands.
Giuseppe Giovanni Nardone, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
Aurora Santin, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
Helena Schmidt, Department of Molecular Biology and Biochemistry, Medical University Graz, Graz, Styria, Austria.
Botong Shen, Laboratory of Epidemiology and Population Sciences, Health Disparities Research Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Tamar Sofer, Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA.
Quan Sun, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Document Type

Journal Article

Publication Date

1-10-2026

Journal

HGG advances

Volume

7

Issue

2

DOI

10.1016/j.xhgg.2026.100566

Keywords

blood pressure; depressive symptomatology; gene-environment interactions; genetics; genome-wide association study; hypertension; multi-ancestry

Abstract

Gene-environment interactions may enhance our understanding of blood pressure (BP) biology. We conducted a meta-analysis of multi-population genome-wide association studies (GWASs) of BP traits accounting for gene-depressive symptomatology (DEPR) interactions. Our study included 564,680 adults from 67 cohorts and four population backgrounds: African (5%), Asian (7%), European (85%), and Hispanic (3%). We discovered seven previously unreported BP loci showing gene-DEPR interaction. These loci mapped to genes implicated in neurogenesis (TGFA and CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6 and DBI). We also showed evidence for gene-DEPR interaction at nine known BP loci, further suggesting links between mood disturbance and BP regulation. Of the 16 identified loci, 11 were derived from non-European populations. Post-GWAS analyses prioritized 36 genes, including genes involved in synaptic functions (DOCK4 and MAGI2) and neuronal signaling (CCK, UGDH, and SLC01A2). Integrative druggability analyses identified 11 druggable candidate gene targets linked to pathways involved in mood disorders as well as known anti-hypertensive drugs. Our findings emphasize the importance of considering gene-DEPR interactions on BP, particularly in non-European populations. Our prioritized genes and druggable targets highlight biological pathways connecting mood disorders and hypertension and suggest opportunities for BP drug repurposing and risk factor prevention, especially in individuals with DEPR.

Department

Medicine

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