A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations

Million Veteran Program; Pavithra Nagarajan; Thomas W Winkler; Amy R Bentley; Clint L Miller; Aldi T Kraja; Karen Schwander; Songmi Lee; Wenyi Wang; Michael R Brown; John L Morrison; Ayush Giri; Jeffrey R O'Connell; Traci M Bartz; Lisa de Las Fuentes; Valborg Gudmundsdottir; Xiuqing Guo; Sarah E Harris; Zhijie Huang; Mart Kals; Minjung Kho; Christophe Lefevre; Jian'an Luan; Leo-Pekka Lyytikäinen; Massimo Mangino; Yuri Milaneschi; Nicholette D Palmer; Varun Rao; Rainer Rauramaa; Botong Shen; Stefan Stadler; Quan Sun; Jingxian Tang; Sébastien Thériault; Adriaan van der Graaf; Peter J van der Most; Yujie Wang; Stefan Weiss; Kenneth E Westerman; Qian Yang; Tabara Yasuharu; Wei Zhao; Wanying Zhu; Drew Altschul; Md Abu Yusuf Ansari; Anna D Argoty-Pantoja; Zekai Chen; Paul S de Vries; Ilja M Nolte; Brenda Wjh Penninx; Harold Snieder; Raymond Noordam; Heming Wang

doi:10.1038/s41380-025-02954-w

A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations

Million Veteran Program, Pavithra Nagarajan, Thomas W Winkler, Amy R Bentley, Clint L Miller, Aldi T Kraja, Karen Schwander, Songmi Lee, Wenyi Wang, Michael R Brown, John L Morrison, Ayush Giri, Jeffrey R O'Connell, Traci M Bartz, Lisa de Las Fuentes, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Zhijie Huang, Mart KalsMinjung Kho, Christophe Lefevre, Jian'an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Yuri Milaneschi, Nicholette D Palmer, Varun Rao, Rainer Rauramaa, Botong Shen, Stefan Stadler, Quan Sun, Jingxian Tang, Sébastien Thériault, Adriaan van der Graaf, Peter J van der Most, Yujie Wang, Stefan Weiss, Kenneth E Westerman, Qian Yang, Tabara Yasuharu, Wei Zhao, Wanying Zhu, Drew Altschul, Md Abu Yusuf Ansari, Anna D Argoty-Pantoja, Zekai Chen, Paul S de Vries, Ilja M Nolte, Brenda Wjh Penninx, Harold Snieder, Raymond Noordam, Heming Wang^*

^*Corresponding author for this work

Life Course Epidemiology (LCE)

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

Original language	English
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-025-02954-w
Publication status	E-pub ahead of print - 4-Apr-2025

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Million Veteran Program, Nagarajan, P., Winkler, T. W., Bentley, A. R., Miller, C. L., Kraja, A. T., Schwander, K., Lee, S., Wang, W., Brown, M. R., Morrison, J. L., Giri, A., O'Connell, J. R., Bartz, T. M., de Las Fuentes, L., Gudmundsdottir, V., Guo, X., Harris, S. E., Huang, Z., ... Wang, H. (2025). A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations. Molecular Psychiatry. Advance online publication. https://doi.org/10.1038/s41380-025-02954-w

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title = "A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations",

abstract = "Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.",

author = "{Million Veteran Program} and Pavithra Nagarajan and Winkler, {Thomas W} and Bentley, {Amy R} and Miller, {Clint L} and Kraja, {Aldi T} and Karen Schwander and Songmi Lee and Wenyi Wang and Brown, {Michael R} and Morrison, {John L} and Ayush Giri and O'Connell, {Jeffrey R} and Bartz, {Traci M} and {de Las Fuentes}, Lisa and Valborg Gudmundsdottir and Xiuqing Guo and Harris, {Sarah E} and Zhijie Huang and Mart Kals and Minjung Kho and Christophe Lefevre and Jian'an Luan and Leo-Pekka Lyytik{\"a}inen and Massimo Mangino and Yuri Milaneschi and Palmer, {Nicholette D} and Varun Rao and Rainer Rauramaa and Botong Shen and Stefan Stadler and Quan Sun and Jingxian Tang and S{\'e}bastien Th{\'e}riault and {van der Graaf}, Adriaan and {van der Most}, {Peter J} and Yujie Wang and Stefan Weiss and Westerman, {Kenneth E} and Qian Yang and Tabara Yasuharu and Wei Zhao and Wanying Zhu and Drew Altschul and Ansari, {Md Abu Yusuf} and Argoty-Pantoja, {Anna D} and Zekai Chen and {de Vries}, {Paul S} and Nolte, {Ilja M} and Penninx, {Brenda Wjh} and Harold Snieder and Raymond Noordam and Heming Wang",

note = "{\textcopyright} 2025. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2025",

month = apr,

day = "4",

doi = "10.1038/s41380-025-02954-w",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

}

Million Veteran Program, Nagarajan, P, Winkler, TW, Bentley, AR, Miller, CL, Kraja, AT, Schwander, K, Lee, S, Wang, W, Brown, MR, Morrison, JL, Giri, A, O'Connell, JR, Bartz, TM, de Las Fuentes, L, Gudmundsdottir, V, Guo, X, Harris, SE, Huang, Z, Kals, M, Kho, M, Lefevre, C, Luan, J, Lyytikäinen, L-P, Mangino, M, Milaneschi, Y, Palmer, ND, Rao, V, Rauramaa, R, Shen, B, Stadler, S, Sun, Q, Tang, J, Thériault, S, van der Graaf, A , van der Most, PJ, Wang, Y, Weiss, S, Westerman, KE, Yang, Q, Yasuharu, T, Zhao, W, Zhu, W, Altschul, D, Ansari, MAY, Argoty-Pantoja, AD , Chen, Z, de Vries, PS, Nolte, IM, Penninx, BW, Snieder, H, Noordam, R & Wang, H 2025, 'A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations', Molecular Psychiatry. https://doi.org/10.1038/s41380-025-02954-w

TY - JOUR

T1 - A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations

AU - Million Veteran Program

AU - Nagarajan, Pavithra

AU - Winkler, Thomas W

AU - Bentley, Amy R

AU - Miller, Clint L

AU - Kraja, Aldi T

AU - Schwander, Karen

AU - Lee, Songmi

AU - Wang, Wenyi

AU - Brown, Michael R

AU - Morrison, John L

AU - Giri, Ayush

AU - O'Connell, Jeffrey R

AU - Bartz, Traci M

AU - de Las Fuentes, Lisa

AU - Gudmundsdottir, Valborg

AU - Guo, Xiuqing

AU - Harris, Sarah E

AU - Huang, Zhijie

AU - Kals, Mart

AU - Kho, Minjung

AU - Lefevre, Christophe

AU - Luan, Jian'an

AU - Lyytikäinen, Leo-Pekka

AU - Mangino, Massimo

AU - Milaneschi, Yuri

AU - Palmer, Nicholette D

AU - Rao, Varun

AU - Rauramaa, Rainer

AU - Shen, Botong

AU - Stadler, Stefan

AU - Sun, Quan

AU - Tang, Jingxian

AU - Thériault, Sébastien

AU - van der Graaf, Adriaan

AU - van der Most, Peter J

AU - Wang, Yujie

AU - Weiss, Stefan

AU - Westerman, Kenneth E

AU - Yang, Qian

AU - Yasuharu, Tabara

AU - Zhao, Wei

AU - Zhu, Wanying

AU - Altschul, Drew

AU - Ansari, Md Abu Yusuf

AU - Argoty-Pantoja, Anna D

AU - Chen, Zekai

AU - de Vries, Paul S

AU - Nolte, Ilja M

AU - Penninx, Brenda Wjh

AU - Snieder, Harold

AU - Noordam, Raymond

AU - Wang, Heming

PY - 2025/4/4

Y1 - 2025/4/4

N2 - Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

AB - Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

U2 - 10.1038/s41380-025-02954-w

DO - 10.1038/s41380-025-02954-w

M3 - Article

C2 - 40181193

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations

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