Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure
Authors: Wang Heming , Noordam Raymond , Cade Brian E , Schwander Karen , Winkler Thomas W , Lee Jiwon , Sung Yun Ju , Bentley Amy R. , Manning Alisa K , Aschard Hugues , Kilpeläinen Tuomas O , Ilkov Marjan , Brown Michael R , Horimoto Andrea R , Richard Melissa , Bartz Traci M , Vojinovic Dina , Lim Elise , Nierenberg Jovia L , Liu Yongmei , Chitrala Kumaraswamynaidu , Rankinen Tuomo , Musani Solomon K , Franceschini Nora , Rauramaa Rainer , Alver Maris , Zee Phyllis , Harris Sarah E , van der Most Peter J , Nolte Ilja M , Munroe Patricia B , Palmer Nicholette D , Kühnel Brigitte , Weiss Stefan , Wen Wanqing , Hall Kelly A , Lyytikäinen Leo-Pekka , O’Connell Jeff , Eiriksdottir Gudny , Launer Lenore J , de Vries Paul S , Arking Dan E , Chen Han , Boerwinkle Eric , Krieger Jose E , Schreiner Pamela J , Sidney Stephen S , Shikany James M , Rice Kenneth , Chen Yii-Der Ida , Gharib Sina A , Bis Joshua C , Luik Annemarie I , Ikram M Arfan , Uitterlinden André G , Amin Najaf , Xu Hanfei , Levy Daniel , He Jiang , Lohman Kurt K , Zonderman Alan B , Rice Treva K , Sims Mario , Wilson Gregory , Sofer Tamar , Rich Stephen S , Palmas Walter , Yao Jie , Guo Xiuqing , Rotter Jerome I , Biermasz Nienke R , Mook-Kanamori Dennis O , Martin Lisa W , Barac Ana , Wallace Robert B , Gottlieb Daniel , Komulainen Pirjo , Heikkinen Sami , Mägi Reedik , Milani Lili , Metspalu Andres , Starr John M , Milaneschi Yuri , Waken RJ , Gao Chuan , Waldenberger Melanie , Peters Annette , Strauch Konstantin , Meitinger Thomas , Roenneberg Till , Völker Uwe , Dörr Marcus , Shu Xiao-Ou , Mukherjee Sutapa , Hillman David R , Kähönen Mika , Wagenknecht Lynne E , Gieger Christian , Grabe Hans J , Zheng Wei , Palmer Lyle J , Lehtimäki Terho , Gudnason Vilmundur , Morrison Alanna C , Pereira Alexandre C , Fornage Myriam , Psaty Bruce M , van Duijn Cornelia M , Liu Ching-Ti , Kelly Tanika N , Evans Michele K , Bouchard Claude , Fox Ervin R , Kooperberg Charles , Zhu Xiaofeng , Lakka Timo A , Esko Tõnu , North Kari E , Deary Ian J , Snieder Harold , Penninx Brenda WJH , Gauderman James , Rao Dabeeru C , Redline Susan , van Heemst Diana 
Published: May 2020

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 (Pint< 5×10−8). 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 (Pint< 5×10−8). 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) includingNME7, FAM208A, MKLN1, CEP164, andRGL3/ELAVL3(Pint< 5×10−8). This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.