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, Tõnu 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 journalArticlepeer-review

4 Scopus citations


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 languageEnglish (US)
Pages (from-to)6293-6304
Number of pages12
JournalMolecular psychiatry
Issue number11
Early online dateApr 15 2021
StatePublished - Nov 2021

Bibliographical 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:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't


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