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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 Pjoint < 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 (Pint < 5 × 10−8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 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 (Pint < 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)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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