Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure

Heming Wang; Raymond Noordam; Brian E. Cade; Karen Schwander; Thomas W. Winkler; Jiwon Lee; Yun Ju Sung; Amy R. Bentley; Alisa K. Manning; Hugues Aschard; Tuomas O. Kilpeläinen; Marjan Ilkov; Michael R. Brown; Andrea R. Horimoto; Melissa Richard; Traci M. Bartz; Dina Vojinovic; Elise Lim; Jovia L. Nierenberg; Yongmei Liu; Kumaraswamynaidu Chitrala; Tuomo Rankinen; Solomon K. Musani; Nora Franceschini; Rainer Rauramaa; Maris Alver; Phyllis C. Zee; Sarah E. Harris; Peter J. van der Most; Ilja M. Nolte; Patricia B. Munroe; Nicholette D. Palmer; Brigitte Kühnel; Stefan Weiss; Wanqing Wen; Kelly A. Hall; Leo-Pekka Lyytikäinen; Jeff O’Connell; Gudny Eiriksdottir; Lenore J. Launer; Paul S. de Vries; Dan E. Arking; Han Chen; Eric Boerwinkle; Jose E. Krieger; Pamela J. Schreiner; Stephen Sidney; James M. Shikany; Kenneth Rice; Yii-Der Ida Chen; Sina A. Gharib; Joshua C. Bis; Annemarie I. Luik; M. Arfan Ikram; André G. Uitterlinden; Najaf Amin; Hanfei Xu; Daniel Levy; Jiang He; Kurt K. Lohman; Alan B. Zonderman; Treva K. Rice; Mario Sims; Gregory Wilson; Tamar Sofer; Stephen S. Rich; Walter Palmas; Jie Yao; Xiuqing Guo; Jerome I. Rotter; Nienke R. Biermasz; Dennis O. Mook-Kanamori; Lisa W. Martin; Ana Barac; Robert B. Wallace; Daniel J. Gottlieb; Pirjo Komulainen; Sami Heikkinen; Reedik Mägi; Lili Milani; Andres Metspalu; John M. Starr; Yuri Milaneschi; R. J. Waken; Chuan Gao; Melanie Waldenberger; Annette Peters; Konstantin Strauch; Thomas Meitinger; Till Roenneberg; Uwe Völker; Marcus Dörr; Xiao-Ou Shu; Sutapa Mukherjee; David R. Hillman; Mika Kähönen; Lynne E. Wagenknecht; Christian Gieger; Hans J. Grabe; Wei Zheng; Lyle J. Palmer; Terho Lehtimäki; Vilmundur Gudnason; Alanna C. Morrison; Alexandre C. Pereira; Myriam Fornage; Bruce M. Psaty; Cornelia M. van Duijn; Ching-Ti Liu; Tanika N. Kelly; Michele K. Evans; Claude Bouchard; Ervin R. Fox; Charles Kooperberg; Xiaofeng Zhu; Timo A. Lakka; T. nu Esko; Kari E. North; Ian J. Deary; Harold Snieder; Brenda W. J. H. Penninx; W. James Gauderman; Dabeeru C. Rao; Susan Redline; Diana van Heemst

doi:https://doi.org/10.1038/s41380-021-01087-0

Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure

Heming Wang, Raymond Noordam, Brian E. Cade, Karen Schwander, Thomas W. Winkler, Jiwon Lee, Yun Ju Sung, Amy R. Bentley, Alisa K. Manning, Hugues Aschard, Tuomas O. Kilpeläinen, Marjan Ilkov, Michael R. Brown, Andrea R. Horimoto, Melissa Richard, Traci M. Bartz, Dina Vojinovic, Elise Lim, Jovia L. Nierenberg, Yongmei LiuKumaraswamynaidu Chitrala, Tuomo Rankinen, Solomon K. Musani, Nora Franceschini, Rainer Rauramaa, Maris Alver, Phyllis C. Zee, Sarah E. Harris, Peter J. van der Most, Ilja M. Nolte, Patricia B. Munroe, Nicholette D. Palmer, Brigitte Kühnel, Stefan Weiss, Wanqing Wen, Kelly A. Hall, Leo-Pekka Lyytikäinen, Jeff O’Connell, Gudny Eiriksdottir, Lenore J. Launer, Paul S. de Vries, Dan E. Arking, Han Chen, Eric Boerwinkle, Jose E. Krieger, Pamela J. Schreiner, Stephen Sidney, James M. Shikany, Kenneth Rice, Yii-Der Ida Chen, Sina A. Gharib, Joshua C. Bis, Annemarie I. Luik, M. Arfan Ikram, André G. Uitterlinden, Najaf Amin, Hanfei Xu, Daniel Levy, Jiang He, Kurt K. Lohman, Alan B. Zonderman, Treva K. Rice, Mario Sims, Gregory Wilson, Tamar Sofer, Stephen S. Rich, Walter Palmas, Jie Yao, Xiuqing Guo, Jerome I. Rotter, Nienke R. Biermasz, Dennis O. Mook-Kanamori, Lisa W. Martin, Ana Barac, Robert B. Wallace, Daniel J. Gottlieb, Pirjo Komulainen, Sami Heikkinen, Reedik Mägi, Lili Milani, Andres Metspalu, John M. Starr, Yuri Milaneschi, R. J. Waken, Chuan Gao, Melanie Waldenberger, Annette Peters, Konstantin Strauch, Thomas Meitinger, Till Roenneberg, Uwe Völker, Marcus Dörr, Xiao-Ou Shu, Sutapa Mukherjee, David R. Hillman, Mika Kähönen, Lynne E. Wagenknecht, Christian Gieger, Hans J. Grabe, Wei Zheng, Lyle J. Palmer, Terho Lehtimäki, Vilmundur Gudnason, Alanna C. Morrison, Alexandre C. Pereira, Myriam Fornage, Bruce M. Psaty, Cornelia M. van Duijn, Ching-Ti Liu, Tanika N. Kelly, Michele K. Evans, Claude Bouchard, Ervin R. Fox, Charles Kooperberg, Xiaofeng Zhu, Timo A. Lakka, T. nu Esko, Kari E. North, Ian J. Deary, Harold Snieder, Brenda W. J. H. Penninx, W. James Gauderman, Dabeeru C. Rao, Susan Redline, Diana van Heemst

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

11 Citations (Scopus)

Abstract

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P _joint < 5 × 10 ⁻⁸), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P _int < 5 × 10 ⁻⁸). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P _int = 2 × 10 ⁻⁶). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P _int < 10 ⁻³). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep–wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Original language	English
Pages (from-to)	6293-6304
Number of pages	12
Journal	Molecular psychiatry
Volume	26
Issue number	11
Early online date	2021
DOIs	https://doi.org/10.1038/s41380-021-01087-0
Publication status	Published - Nov 2021

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Wang, H., Noordam, R., Cade, B. E., Schwander, K., Winkler, T. W., Lee, J., Sung, Y. J., Bentley, A. R., Manning, A. K., Aschard, H., Kilpeläinen, T. O., Ilkov, M., Brown, M. R., Horimoto, A. R., Richard, M., Bartz, T. M., Vojinovic, D., Lim, E., Nierenberg, J. L., ... van Heemst, D. (2021). Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure. Molecular psychiatry, 26(11), 6293-6304. Advance online publication. https://doi.org/10.1038/s41380-021-01087-0

@article{d7f98ba5b8c248bd881ff786294a6f43,

title = "Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure",

abstract = "Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P joint < 5 × 10 −8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P int < 5 × 10 −8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P int = 2 × 10 −6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P int < 10 −3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep–wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation. ",

author = "Heming Wang and Raymond Noordam and Cade, {Brian E.} and Karen Schwander and Winkler, {Thomas W.} and Jiwon Lee and Sung, {Yun Ju} and Bentley, {Amy R.} and Manning, {Alisa K.} and Hugues Aschard and Kilpel{\"a}inen, {Tuomas O.} and Marjan Ilkov and Brown, {Michael R.} and Horimoto, {Andrea R.} and Melissa Richard and Bartz, {Traci M.} and Dina Vojinovic and Elise Lim and Nierenberg, {Jovia L.} and Yongmei Liu and Kumaraswamynaidu Chitrala and Tuomo Rankinen and Musani, {Solomon K.} and Nora Franceschini and Rainer Rauramaa and Maris Alver and Zee, {Phyllis C.} and Harris, {Sarah E.} and {van der Most}, {Peter J.} and Nolte, {Ilja M.} and Munroe, {Patricia B.} and Palmer, {Nicholette D.} and Brigitte K{\"u}hnel and Stefan Weiss and Wanqing Wen and Hall, {Kelly A.} and Leo-Pekka Lyytik{\"a}inen and Jeff O{\textquoteright}Connell and Gudny Eiriksdottir and Launer, {Lenore J.} and {de Vries}, {Paul S.} and Arking, {Dan E.} and Han Chen and Eric Boerwinkle and Krieger, {Jose E.} and Schreiner, {Pamela J.} and Stephen Sidney and Shikany, {James M.} and Kenneth Rice and Chen, {Yii-Der Ida} and Gharib, {Sina A.} and Bis, {Joshua C.} and Luik, {Annemarie I.} and Ikram, {M. Arfan} and Uitterlinden, {Andr{\'e} G.} and Najaf Amin and Hanfei Xu and Daniel Levy and Jiang He and Lohman, {Kurt K.} and Zonderman, {Alan B.} and Rice, {Treva K.} and Mario Sims and Gregory Wilson and Tamar Sofer and Rich, {Stephen S.} and Walter Palmas and Jie Yao and Xiuqing Guo and Rotter, {Jerome I.} and Biermasz, {Nienke R.} and Mook-Kanamori, {Dennis O.} and Martin, {Lisa W.} and Ana Barac and Wallace, {Robert B.} and Gottlieb, {Daniel J.} and Pirjo Komulainen and Sami Heikkinen and Reedik M{\"a}gi and Lili Milani and Andres Metspalu and Starr, {John M.} and Yuri Milaneschi and Waken, {R. J.} and Chuan Gao and Melanie Waldenberger and Annette Peters and Konstantin Strauch and Thomas Meitinger and Till Roenneberg and Uwe V{\"o}lker and Marcus D{\"o}rr and Xiao-Ou Shu and Sutapa Mukherjee and Hillman, {David R.} and Mika K{\"a}h{\"o}nen and Wagenknecht, {Lynne E.} and Christian Gieger and Grabe, {Hans J.} and Wei Zheng and Palmer, {Lyle J.} and Terho Lehtim{\"a}ki and Vilmundur Gudnason and Morrison, {Alanna C.} and Pereira, {Alexandre C.} and Myriam Fornage and Psaty, {Bruce M.} and {van Duijn}, {Cornelia M.} and Ching-Ti Liu and Kelly, {Tanika N.} and Evans, {Michele K.} and Claude Bouchard and Fox, {Ervin R.} and Charles Kooperberg and Xiaofeng Zhu and Lakka, {Timo A.} and Esko, {T. nu} and North, {Kari E.} and Deary, {Ian J.} and Harold Snieder and Penninx, {Brenda W. J. H.} and Gauderman, {W. James} and Rao, {Dabeeru C.} and Susan Redline and {van Heemst}, Diana",

note = "Funding Information: Acknowledgements This project was supported by the US National Heart, Lung, and Blood Institute (NHLBI) R01HL118305. HW and SR were supported by NHLBI R35HL135818. BEC was supported by NHLBI K01HL135405. ARB was supported by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). D. v.H. was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). The CHARGE cohorts were supported in part by NHLBI infrastructure grant HL105756. Study-specific acknowledgments can be found in the Supplementary Notes. Funding Information: Conflict of interest DOMK is a part-time research consultant at Metabolon, Inc. BMP serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = nov,

doi = "https://doi.org/10.1038/s41380-021-01087-0",

language = "English",

volume = "26",

pages = "6293--6304",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "11",

}

Wang, H, Noordam, R, Cade, BE, Schwander, K, Winkler, TW, Lee, J, Sung, YJ, Bentley, AR, Manning, AK, Aschard, H, Kilpeläinen, TO, Ilkov, M, Brown, MR, Horimoto, AR, Richard, M, Bartz, TM, Vojinovic, D, Lim, E, Nierenberg, JL, Liu, Y, Chitrala, K, Rankinen, T, Musani, SK, Franceschini, N, Rauramaa, R, Alver, M, Zee, PC, Harris, SE, van der Most, PJ, Nolte, IM, Munroe, PB, Palmer, ND, Kühnel, B, Weiss, S, Wen, W, Hall, KA, Lyytikäinen, L-P, O’Connell, J, Eiriksdottir, G, Launer, LJ, de Vries, PS, Arking, DE, Chen, H, Boerwinkle, E, Krieger, JE, Schreiner, PJ, Sidney, S, Shikany, JM, Rice, K, Chen, Y-DI, Gharib, SA, Bis, JC, Luik, AI, Ikram, MA, Uitterlinden, AG, Amin, N, Xu, H, Levy, D, He, J, Lohman, KK, Zonderman, AB, Rice, TK, Sims, M, Wilson, G, Sofer, T, Rich, SS, Palmas, W, Yao, J, Guo, X, Rotter, JI, Biermasz, NR, Mook-Kanamori, DO, Martin, LW, Barac, A, Wallace, RB, Gottlieb, DJ, Komulainen, P, Heikkinen, S, Mägi, R, Milani, L, Metspalu, A, Starr, JM, Milaneschi, Y, Waken, RJ, Gao, C, Waldenberger, M, Peters, A, Strauch, K, Meitinger, T, Roenneberg, T, Völker, U, Dörr, M, Shu, X-O, Mukherjee, S, Hillman, DR, Kähönen, M, Wagenknecht, LE, Gieger, C, Grabe, HJ, Zheng, W, Palmer, LJ, Lehtimäki, T, Gudnason, V, Morrison, AC, Pereira, AC, Fornage, M, Psaty, BM, van Duijn, CM, Liu, C-T, Kelly, TN, Evans, MK, Bouchard, C, Fox, ER, Kooperberg, C, Zhu, X, Lakka, TA, Esko, TN, North, KE, Deary, IJ, Snieder, H, Penninx, BWJH, Gauderman, WJ, Rao, DC, Redline, S & van Heemst, D 2021, 'Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure', Molecular psychiatry, vol. 26, no. 11, pp. 6293-6304. https://doi.org/10.1038/s41380-021-01087-0

TY - JOUR

T1 - Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure

AU - Wang, Heming

AU - Noordam, Raymond

AU - Cade, Brian E.

AU - Schwander, Karen

AU - Winkler, Thomas W.

AU - Lee, Jiwon

AU - Sung, Yun Ju

AU - Bentley, Amy R.

AU - Manning, Alisa K.

AU - Aschard, Hugues

AU - Kilpeläinen, Tuomas O.

AU - Ilkov, Marjan

AU - Brown, Michael R.

AU - Horimoto, Andrea R.

AU - Richard, Melissa

AU - Bartz, Traci M.

AU - Vojinovic, Dina

AU - Lim, Elise

AU - Nierenberg, Jovia L.

AU - Liu, Yongmei

AU - Chitrala, Kumaraswamynaidu

AU - Rankinen, Tuomo

AU - Musani, Solomon K.

AU - Franceschini, Nora

AU - Rauramaa, Rainer

AU - Alver, Maris

AU - Zee, Phyllis C.

AU - Harris, Sarah E.

AU - van der Most, Peter J.

AU - Nolte, Ilja M.

AU - Munroe, Patricia B.

AU - Palmer, Nicholette D.

AU - Kühnel, Brigitte

AU - Weiss, Stefan

AU - Wen, Wanqing

AU - Hall, Kelly A.

AU - Lyytikäinen, Leo-Pekka

AU - O’Connell, Jeff

AU - Eiriksdottir, Gudny

AU - Launer, Lenore J.

AU - de Vries, Paul S.

AU - Arking, Dan E.

AU - Chen, Han

AU - Boerwinkle, Eric

AU - Krieger, Jose E.

AU - Schreiner, Pamela J.

AU - Sidney, Stephen

AU - Shikany, James M.

AU - Rice, Kenneth

AU - Chen, Yii-Der Ida

AU - Gharib, Sina A.

AU - Bis, Joshua C.

AU - Luik, Annemarie I.

AU - Ikram, M. Arfan

AU - Uitterlinden, André G.

AU - Amin, Najaf

AU - Xu, Hanfei

AU - Levy, Daniel

AU - He, Jiang

AU - Lohman, Kurt K.

AU - Zonderman, Alan B.

AU - Rice, Treva K.

AU - Sims, Mario

AU - Wilson, Gregory

AU - Sofer, Tamar

AU - Rich, Stephen S.

AU - Palmas, Walter

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Rotter, Jerome I.

AU - Biermasz, Nienke R.

AU - Mook-Kanamori, Dennis O.

AU - Martin, Lisa W.

AU - Barac, Ana

AU - Wallace, Robert B.

AU - Gottlieb, Daniel J.

AU - Komulainen, Pirjo

AU - Heikkinen, Sami

AU - Mägi, Reedik

AU - Milani, Lili

AU - Metspalu, Andres

AU - Starr, John M.

AU - Milaneschi, Yuri

AU - Waken, R. J.

AU - Gao, Chuan

AU - Waldenberger, Melanie

AU - Peters, Annette

AU - Strauch, Konstantin

AU - Meitinger, Thomas

AU - Roenneberg, Till

AU - Völker, Uwe

AU - Dörr, Marcus

AU - Shu, Xiao-Ou

AU - Mukherjee, Sutapa

AU - Hillman, David R.

AU - Kähönen, Mika

AU - Wagenknecht, Lynne E.

AU - Gieger, Christian

AU - Grabe, Hans J.

AU - Zheng, Wei

AU - Palmer, Lyle J.

AU - Lehtimäki, Terho

AU - Gudnason, Vilmundur

AU - Morrison, Alanna C.

AU - Pereira, Alexandre C.

AU - Fornage, Myriam

AU - Psaty, Bruce M.

AU - van Duijn, Cornelia M.

AU - Liu, Ching-Ti

AU - Kelly, Tanika N.

AU - Evans, Michele K.

AU - Bouchard, Claude

AU - Fox, Ervin R.

AU - Kooperberg, Charles

AU - Zhu, Xiaofeng

AU - Lakka, Timo A.

AU - Esko, T. nu

AU - North, Kari E.

AU - Deary, Ian J.

AU - Snieder, Harold

AU - Penninx, Brenda W. J. H.

AU - Gauderman, W. James

AU - Rao, Dabeeru C.

AU - Redline, Susan

AU - van Heemst, Diana

N1 - Funding Information: Acknowledgements This project was supported by the US National Heart, Lung, and Blood Institute (NHLBI) R01HL118305. HW and SR were supported by NHLBI R35HL135818. BEC was supported by NHLBI K01HL135405. ARB was supported by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). D. v.H. was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). The CHARGE cohorts were supported in part by NHLBI infrastructure grant HL105756. Study-specific acknowledgments can be found in the Supplementary Notes. Funding Information: Conflict of interest DOMK is a part-time research consultant at Metabolon, Inc. BMP serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/11

Y1 - 2021/11

N2 - Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P joint < 5 × 10 −8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P int < 5 × 10 −8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P int = 2 × 10 −6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P int < 10 −3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep–wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

AB - Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P joint < 5 × 10 −8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P int < 5 × 10 −8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P int = 2 × 10 −6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P int < 10 −3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep–wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

UR - http://www.scopus.com/inward/record.url?scp=85104697425&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41380-021-01087-0

DO - https://doi.org/10.1038/s41380-021-01087-0

M3 - Article

C2 - 33859359

SN - 1359-4184

VL - 26

SP - 6293

EP - 6304

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 11

ER -

Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure

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