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

Heming Wang (1, 2) , Raymond Noordam , Brian Cade , Karen Schwander , Thomas Winkler , Jiwon Lee (3) , Yun Ju Sung (4) , Amy Bentley , Alisa Manning , Hugues Aschard (5) , Tuomas Kilpeläinen , Marjan Ilkov , Michael Brown , Andrea Horimoto , Melissa Richard , Traci Bartz , Dina Vojinovic , Elise Lim , Jovia Nierenberg , Yongmei Liu , Kumaraswamynaidu Chitrala , Tuomo Rankinen , Solomon Musani , Nora Franceschini , Rainer Rauramaa , Maris Alver , Phyllis Zee , Sarah Harris , Peter van Der Most , Ilja Nolte , Patricia Munroe , Nicholette Palmer , Brigitte Kühnel , Stefan Weiss , Wanqing Wen , Kelly Hall , Leo-Pekka Lyytikäinen , Jeff O'Connell , Gudny Eiriksdottir , Lenore Launer , Paul de Vries , Dan Arking , Han Chen , Eric Boerwinkle , Jose Krieger , Pamela Schreiner , Stephen Sidney , James Shikany , Kenneth Rice , Yii-Der Ida Chen , Sina Gharib , Joshua Bis , Annemarie Luik , M Arfan Ikram , André Uitterlinden , Najaf Amin , Hanfei Xu , Daniel Levy , Jiang He , Kurt Lohman , Alan Zonderman , Treva Rice , Mario Sims , Gregory Wilson , Tamar Sofer , Stephen Rich , Walter Palmas , Jie Yao , Xiuqing Guo , Jerome Rotter , Nienke Biermasz , Dennis Mook-Kanamori , Lisa Martin , Ana Barac , Robert Wallace , Daniel Gottlieb , Pirjo Komulainen , Sami Heikkinen , Reedik Mägi , Lili Milani , Andres Metspalu , John Starr , Yuri Milaneschi , R. Waken , Chuan Gao , Melanie Waldenberger , Annette Peters , Konstantin Strauch , Thomas Meitinger , Till Roenneberg , Uwe Völker , Marcus Dörr , Xiao-Ou Shu , Sutapa Mukherjee , David Hillman , Mika Kähönen , Lynne Wagenknecht , Christian Gieger , Hans Grabe , Wei Zheng , Lyle Palmer , Terho Lehtimäki , Vilmundur Gudnason , Alanna Morrison , Alexandre Pereira , Myriam Fornage , Bruce Psaty , Cornelia van Duijn , Ching-Ti Liu , Tanika Kelly , Michele Evans , Claude Bouchard , Ervin Fox , Charles Kooperberg , Xiaofeng Zhu , Timo Lakka , Tõnu Esko , Kari North , Ian Deary , Harold Snieder , Brenda Penninx , W James Gauderman , Dabeeru Rao , Susan Redline , Diana van Heemst (6)

1 HMS - Harvard Medical School [Boston]
2 Broad Institute [Cambridge]
3 Hallym University
4 Department of Educational Psychology and Counseling
5 Département de Biologie Computationnelle - Department of Computational Biology
6 Leiden University Medical Center (LUMC)

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.

Domains: Human genetics; Santé publique et épidémiologie; Methodology [stat.ME]; Applications [stat.AP]; Bioinformatics [q-bio.QM]

Heming Wang, Raymond Noordam, Brian Cade, Karen Schwander, Thomas Winkler, et al.. Multi-ancestry genome-wide gene–sleep interactions identify novel loci for blood pressure. Molecular Psychiatry, 2021, 26 (11), pp.6293-6304. ⟨10.1038/s41380-021-01087-0⟩. ⟨pasteur-03278749⟩