A1 Refereed original research article in a scientific journal
A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations
Authors: Lee, Songmi; Miller, Clint L.; Bentley, Amy R.; Brown, Michael R.; Nagarajan, Pavithra; Noordam, Raymond; Morrison, John; Schwander, Karen; Westerman, Kenneth; Kho, Minjung; Kraja, Aldi T.; de Vries, Paul S.; Ammous, Farah; Aschard, Hughes; Bartz, Traci M.; Do, Anh; Dupont, Charles T.; Feitosa, Mary F.; Gudmundsdottir, Valborg; Guo, Xiuqing; Harris, Sarah E.; Hikino, Keiko; Huang, Zhijie; Lefevre, Christophe; Lyytikäinen, Leo-Pekka; Milaneschi, Yuri; Nardone, Giuseppe Giovanni; Santin, Aurora; Schmidt, Helena; Shen, Botong; Sofer, Tamar; Sun, Quan; Tan, Ye An; Tang, Jingxian; Thériault, Sébastien; van der Most, Peter J.; Ware, Erin B.; Weiss, Stefan; Xing, Wang Ya; Yu, Chenglong; Zhao, Wei; Yusuf Ansari, Md Abu; Anugu, Pramod; Attia, John R.; Bazzano, Lydia A.; Bis, Joshua C.; Breyer, Max; Cade, Brian; Chen, Guanjie; Collins, Stacey; Corley, Janie; Davies, Gail; Dörr, Marcus; Du, Jiawen; Edwards, Todd L.; Faquih, Tariq; Faul, Jessica D.; Fohner, Alison E.; Fretts, Amanda M.; Gangireddy, Srushti; Gepner, Adam; Graff, MariaElisa; Hofer, Edith; Homuth, Georg; Hood, Michelle M.; Jie, Xu; Kähönen, Mika; Kardia, Sharon L. R.; Karvonen-Gutierrez, Carrie A.; Launer, Lenore J.; Levy, Daniel; Maheshwari, Maitreiyi; Martin, Lisa W.; Matsuda, Koichi; McNeil, John J.; Nolte, Ilja M.; Okochi, Tomo; Raffield, Laura M.; Raitakari, Olli T.; Risch, Lorenz; Risch, Martin; Roux, Ana Diez; Ruiz-Narvaez, Edward A.; Russ, Tom C.; Saito, Takeo; Schreiner, Pamela J.; Scott, Rodney J.; Shikany, James; Smith, Jennifer A.; Snieder, Harold; Spedicati, Beatrice; Tai, E. Shyong; Taylor, Adele M.; Taylor, Kent D.; Tesolin, Paola; van Dam, Rob M.; Wang, Rujia; Wenbin, Wei; Xie, Tian; Yao, Jie; Young, Kristin L.; Zhang, Ruiyuan; Zonderman, Alan B.; Lifelines Cohort Study; Concas, Maria Pina; Conen, David; Cox, Simon R.; Evans, Michele K.; Fox, Ervin R.; de las Fuentes, Lisa; Giri, Ayush; Girotto, Giorgia; Grabe, Hans J.; Gu, Charles; Gudnason, Vilmundur; Harlow, Sioban D.; Holliday, Elizabeth; Jost, Jonas B.; Lacaze, Paul; Lee, Seunggeun; Lehtimäki, Terho; Li, Changwei; Liu, Ching-Ti; Morrison, Alanna C.; North, Kari E.; Penninx, Brenda W. J. H.; Peyser, Patricia A.; Province, Michael M.; Psaty, Bruce M.; Redline, Susan; Rosendaal, Frits R.; Rotimi, Charles N.; Rotter, Jerome I.; Schmidt, Reinhold; Sim, Xueling; Terao, Chikashi; Weir, David R.; Zhu, Xiaofeng; Franceschini, Nora; O’Connell, Jeffrey R.; Jaquish, Cashell E.; Wang, Heming; Manning, Alisa; Munroe, Patricia B.; Rao, Dabeeru C.; Chen, Han; Gauderman, W. James; Bierut, Laura; Winkler, Thomas W.; Fornage, Myriam
Publisher: Elsevier
Publication year: 2026
Journal: HGG advances
Article number: 100566
Volume: 7
Issue: 2
eISSN: 2666-2477
DOI: https://doi.org/10.1016/j.xhgg.2026.100566
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1016/j.xhgg.2026.100566
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/508598431
Self-archived copy's licence: CC BY NC
Self-archived copy's version: Publisher`s PDF
Gene-environment interactions may enhance our understanding of blood pressure (BP) biology. We conducted a meta-analysis of multi-population genome-wide association studies of BP traits accounting for gene-depressive symptomatology (DEPR) interactions. Our study included 564,680 adults from 67 cohorts and 4 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, CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6, 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 loci were derived from non-European populations. Post-GWAS analyses prioritized 36 genes, including genes involved in synaptic functions (DOCK4, MAGI2) and neuronal signaling (CCK, UGDH, SLC01A2). Integrative druggability analyses identified 11 druggable candidate gene targets linked to pathways involved in mood disorders as well as known antihypertensive 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.
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Funding information in the publication:
This project was largely supported by two grants from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305, R01HL156991, and HL105756. PBM acknowledges support from the National Institute for Health and Care Research (NIHR) Biomedical Research Centre at Barts (NIHR202330). KEN and KLM were provided in part by R01HL142302, R01HL151152, R01DK122503, R01HD057194, R01HG010297, R01HL143885, R01HL163262. NF was supported by R01DK117445, R01MD012765, R01HL163972. Study-specific acknowledgements and funding sources are included in the Supplemental Material.
