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

By 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 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 S 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 Gottlieb, Pirjo Komulainen, Sami Heikkinen, Reedik Mägi, Lili Milani, Andres Metspalu, John M. Starr, Yuri Milaneschi, RJ 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 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 Deary, Harold Snieder, Brenda WJH Penninx, James Gauderman, Dabeeru C Rao, Susan Redline, Diana van Heemst

Posted 31 May 2020
bioRxiv DOI: 10.1101/2020.05.29.123505

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 using 1 degree of freedom (1df) interaction and 2df joint tests. Primary multi-ancestry analyses in 62,969 individuals in stage 1 identified 3 novel loci that were replicated in an additional 59,296 individuals in stage 2, including rs7955964 (FIGNL2/ANKRD33) showing significant 1df interactions with long sleep duration and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) showing significant 1df interactions with short sleep duration. Secondary ancestry-specific two-stage analyses and combined stage 1 and 2 analyses additionally identified 23 novel loci that need external replication, including 3 and 5 loci showing significant 1df interactions with long and short sleep duration, respectively. Multiple genes mapped to our 26 novel loci have known functions in sleep-wake regulation, nervous and cardiometabolic systems. We also identified new gene by long sleep interactions near five known BP loci (≤1Mb) including NME7, FAM208A, MKLN1, CEP164, and RGL3/ELAVL3. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation. ### Competing Interest Statement D.O.M.K. is a part time research consultant at Metabolon, Inc. B.M.P. 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. H.J.G. has received research support from the German Research Foundation (DFG), the German Ministry of Education and Research (BMBF), the DAMP Foundation, Fresenius Medical Care, the EU Joint Programme Neurodegenerative Disorders (JPND) and the European Social Fund (ESF). The remaining authors declare no competing interests.

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