A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations

BioBank Japan Project; Songmi Lee; Clint L Miller; Amy R Bentley; Michael R Brown; Pavithra Nagarajan; Raymond Noordam; John Morrison; Karen Schwander; Kenneth Westerman; Minjung Kho; Aldi T Kraja; Paul S de Vries; Farah Ammous; Hughes Aschard; Traci M Bartz; Anh Do; Charles T Dupont; Mary F Feitosa; Valborg Gudmundsdottir; Xiuqing Guo; Sarah E Harris; Keiko Hikino; Zhijie Huang; Christophe Lefevre; Leo-Pekka Lyytikäinen; Yuri Milaneschi; Giuseppe Giovanni Nardone; Aurora Santin; Helena Schmidt; Botong Shen; Tamar Sofer; Quan Sun; Ye An Tan; Jingxian Tang; Sébastien Thériault; Peter J van der Most; Erin B Ware; Stefan Weiss; Wang Ya Xing; Chenglong Yu; Wei Zhao; Md Abu Yusuf Ansari; Pramod Anugu; John R Attia; Lydia A Bazzano; Ilja M Nolte; Harold Snieder; Rujia Wang; Tian Xie; Brenda Wjh Penninx; Thomas W Winkler; Myriam Fornage

doi:10.1016/j.xhgg.2026.100566

A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations

BioBank Japan Project
, Songmi Lee
, Clint L Miller
, Amy R Bentley
, Michael R Brown
, Pavithra Nagarajan
, Raymond Noordam
, John Morrison
, Karen Schwander
, Kenneth Westerman
, Minjung Kho
, Aldi T Kraja
, Paul S de Vries
, Farah Ammous
, Hughes Aschard
, Traci M Bartz
, Anh Do
, Charles T Dupont
, Mary F Feitosa
, Valborg Gudmundsdottir

Xiuqing Guo, Sarah E Harris, Keiko Hikino, Zhijie Huang, Christophe Lefevre, Leo-Pekka Lyytikäinen, Yuri Milaneschi, Giuseppe Giovanni Nardone, Aurora Santin, Helena Schmidt, Botong Shen, Tamar Sofer, Quan Sun, Ye An Tan, Jingxian Tang, Sébastien Thériault, Peter J van der Most, Erin B Ware, Stefan Weiss, Wang Ya Xing, Chenglong Yu, Wei Zhao, Md Abu Yusuf Ansari, Pramod Anugu, John R Attia, Lydia A Bazzano, Ilja M Nolte, Harold Snieder, Rujia Wang, Tian Xie, Brenda Wjh Penninx, Thomas W Winkler, Myriam Fornage^*

^*Corresponding author voor dit werk

Onderzoeksoutput › Academic › peer review

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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.

Originele taal-2	English
Artikelnummer	100566
Aantal pagina's	17
Tijdschrift	HGG advances
Volume	7
Nummer van het tijdschrift	2
Vroegere onlinedatum	10-jan-2026
DOI's	https://doi.org/10.1016/j.xhgg.2026.100566
Status	Published - 9-apr-2026

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10.1016/j.xhgg.2026.100566Licentie: CC BY-NC-ND

Large-scale blood pressure GWAS accounting Final publisher's version, 4,02 MBLicentie: CC BY-NC-ND

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BioBank Japan Project, Lee, S., Miller, C. L., Bentley, A. R., Brown, M. R., Nagarajan, P., Noordam, R., Morrison, J., Schwander, K., Westerman, K., Kho, M., Kraja, A. T., de Vries, P. S., Ammous, F., Aschard, H., Bartz, T. M., Do, A., Dupont, C. T., Feitosa, M. F., ... Fornage, M. (2026). A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations. HGG advances, 7(2), Artikel 100566. https://doi.org/10.1016/j.xhgg.2026.100566

@article{27474c5b56a24883855fb189b36e1c9f,

title = "A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations",

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 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.",

author = "\{BioBank Japan Project\} and Songmi Lee and Miller, \{Clint L\} and Bentley, \{Amy R\} and Brown, \{Michael R\} and Pavithra Nagarajan and Raymond Noordam and John Morrison and Karen Schwander and Kenneth Westerman and Minjung Kho and Kraja, \{Aldi T\} and \{de Vries\}, \{Paul S\} and Farah Ammous and Hughes Aschard and Bartz, \{Traci M\} and Anh Do and Dupont, \{Charles T\} and Feitosa, \{Mary F\} and Valborg Gudmundsdottir and Xiuqing Guo and Harris, \{Sarah E\} and Keiko Hikino and Zhijie Huang and Christophe Lefevre and Leo-Pekka Lyytik{\"a}inen and Yuri Milaneschi and Nardone, \{Giuseppe Giovanni\} and Aurora Santin and Helena Schmidt and Botong Shen and Tamar Sofer and Quan Sun and Tan, \{Ye An\} and Jingxian Tang and S{\'e}bastien Th{\'e}riault and \{van der Most\}, \{Peter J\} and Ware, \{Erin B\} and Stefan Weiss and Xing, \{Wang Ya\} and Chenglong Yu and Wei Zhao and \{Yusuf Ansari\}, \{Md Abu\} and Pramod Anugu and Attia, \{John R\} and Bazzano, \{Lydia A\} and Nolte, \{Ilja M\} and Harold Snieder and Rujia Wang and Tian Xie and Penninx, \{Brenda Wjh\} and Winkler, \{Thomas W\} and Myriam Fornage",

year = "2026",

month = apr,

day = "9",

doi = "10.1016/j.xhgg.2026.100566",

language = "English",

volume = "7",

journal = "HGG advances",

issn = "2666-2477",

publisher = "American Society for Human Genetics",

number = "2",

}

BioBank Japan Project, Lee, S, Miller, CL, Bentley, AR, Brown, MR, Nagarajan, P, Noordam, R, Morrison, J, Schwander, K, Westerman, K, Kho, M, Kraja, AT, de Vries, PS, Ammous, F, Aschard, H, Bartz, TM, Do, A, Dupont, CT, Feitosa, MF, Gudmundsdottir, V, Guo, X, Harris, SE, Hikino, K, Huang, Z, Lefevre, C, Lyytikäinen, L-P, Milaneschi, Y, Nardone, GG, Santin, A, Schmidt, H, Shen, B, Sofer, T, Sun, Q, Tan, YA, Tang, J, Thériault, S, van der Most, PJ, Ware, EB, Weiss, S, Xing, WY, Yu, C, Zhao, W, Yusuf Ansari, MA, Anugu, P, Attia, JR, Bazzano, LA, Nolte, IM , Snieder, H , Wang, R , Xie, T, Penninx, BW, Winkler, TW & Fornage, M 2026, 'A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations', HGG advances, vol. 7, nr. 2, 100566. https://doi.org/10.1016/j.xhgg.2026.100566

TY - JOUR

T1 - A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations

AU - BioBank Japan Project

AU - Lee, Songmi

AU - Miller, Clint L

AU - Bentley, Amy R

AU - Brown, Michael R

AU - Nagarajan, Pavithra

AU - Noordam, Raymond

AU - Morrison, John

AU - Schwander, Karen

AU - Westerman, Kenneth

AU - Kho, Minjung

AU - Kraja, Aldi T

AU - de Vries, Paul S

AU - Ammous, Farah

AU - Aschard, Hughes

AU - Bartz, Traci M

AU - Do, Anh

AU - Dupont, Charles T

AU - Feitosa, Mary F

AU - Gudmundsdottir, Valborg

AU - Guo, Xiuqing

AU - Harris, Sarah E

AU - Hikino, Keiko

AU - Huang, Zhijie

AU - Lefevre, Christophe

AU - Lyytikäinen, Leo-Pekka

AU - Milaneschi, Yuri

AU - Nardone, Giuseppe Giovanni

AU - Santin, Aurora

AU - Schmidt, Helena

AU - Shen, Botong

AU - Sofer, Tamar

AU - Sun, Quan

AU - Tan, Ye An

AU - Tang, Jingxian

AU - Thériault, Sébastien

AU - van der Most, Peter J

AU - Ware, Erin B

AU - Weiss, Stefan

AU - Xing, Wang Ya

AU - Yu, Chenglong

AU - Zhao, Wei

AU - Yusuf Ansari, Md Abu

AU - Anugu, Pramod

AU - Attia, John R

AU - Bazzano, Lydia A

AU - Nolte, Ilja M

AU - Snieder, Harold

AU - Wang, Rujia

AU - Xie, Tian

AU - Penninx, Brenda Wjh

AU - Winkler, Thomas W

AU - Fornage, Myriam

PY - 2026/4/9

Y1 - 2026/4/9

N2 - 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.

AB - 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.

U2 - 10.1016/j.xhgg.2026.100566

DO - 10.1016/j.xhgg.2026.100566

M3 - Article

C2 - 41520179

SN - 2666-2477

VL - 7

JO - HGG advances

JF - HGG advances

IS - 2

M1 - 100566

ER -

A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations

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