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 , Most Peter J van der , Ware Erin B , Weiss Stefan , Xing Wang Ya , Yu Chenglong , Zhao Wei , Ansari Md Abu Yusuf , 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 LR , 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 , Dam Rob M van , Wang Rujia , Wenbin Wei , Xie Tian , Yao Jie , Young Kristin L , Zhang Ruiyuan , Zonderman Alan B , Project The Biobank Japan , Study Lifelines Cohort , Concas Maria Pina , Conen David , Cox Simon R , Evans Michele K , Fox Ervin R , Fuentes Lisa de las , 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 WJH , 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 
Published: February 2025

Background
Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance of considering psychosocial factors in gene discovery for blood pressure (BP) but was limited in statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association study (GWAS) of BP accounting for gene-depressive symptomatology (DEPR) interactions in a larger and more diverse sample.
Results
Our study included 564,680 adults aged 18 years or older from 67 cohorts and 4 population backgrounds (African (5%), Asian (7%), European (85%), and Hispanic (3%)). We discovered seven novel gene-DEPR interaction loci for BP traits. These loci mapped to genes implicated in neurogenesis (TGFA, CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6, DBI). We also identified 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 African, Asian, or Hispanic 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, including genes implicated in pathways linked to mood disorders as well as gene products targeted by known antihypertensive drugs.
Conclusions
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.