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

MedStar author(s):
Citation: Molecular Psychiatry. 26(11):6293-6304, 2021 11.PMID: 33859359Institution: MedStar Heart & Vascular InstitutenaForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Genome-Wide Association Study | *Hypertension | Blood Pressure/ge [Genetics] | Genetic Loci/ge [Genetics] | Humans | Hypertension/ge [Genetics] | Polymorphism, Single Nucleotide/ge [Genetics] | Sleep/ge [Genetics]Year: 2021ISSN:
  • 1359-4184
Name of journal: Molecular psychiatryAbstract: 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 x 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 x 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 x 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.All authors: Alver M, Amin N, Arking DE, Aschard H, Barac A, Bartz TM, Bentley AR, Biermasz NR, Bis JC, Boerwinkle E, Bouchard C, Brown MR, Cade BE, Chen H, Chen YI, Chitrala K, de Vries PS, Deary IJ, Dorr M, Eiriksdottir G, Esko T, Evans MK, Fornage M, Fox ER, Franceschini N, Gao C, Gauderman WJ, Gharib SA, Gieger C, Gottlieb DJ, Grabe HJ, Gudnason V, Guo X, Hall KA, Harris SE, He J, Heikkinen S, Hillman DR, Horimoto AR, Ikram MA, Ilkov M, Kahonen M, Kelly TN, Kilpelainen TO, Komulainen P, Kooperberg C, Krieger JE, Kuhnel B, Lakka TA, Launer LJ, Lee J, Lehtimaki T, Levy D, Lim E, Liu CT, Liu Y, Lohman KK, Luik AI, Lyytikainen LP, Magi R, Manning AK, Martin LW, Meitinger T, Metspalu A, Milaneschi Y, Milani L, Mook-Kanamori DO, Morrison AC, Mukherjee S, Munroe PB, Musani SK, Nierenberg JL, Nolte IM, Noordam R, North KE, O'Connell J, Palmas W, Palmer LJ, Palmer ND, Penninx BWJH, Pereira AC, Peters A, Psaty BM, Rankinen T, Rao DC, Rauramaa R, Redline S, Rice K, Rice TK, Rich SS, Richard M, Roenneberg T, Rotter JI, Schreiner PJ, Schwander K, Shikany JM, Shu XO, Sidney S, Sims M, Snieder H, Sofer T, Starr JM, Strauch K, Sung YJ, Uitterlinden AG, van der Most PJ, van Duijn CM, van Heemst D, Vojinovic D, Volker U, Wagenknecht LE, Waken RJ, Waldenberger M, Wallace RB, Wang H, Weiss S, Wen W, Wilson G, Winkler TW, Xu H, Yao J, Zee PC, Zheng W, Zhu X, Zonderman ABOriginally published: Molecular Psychiatry. 2021 Apr 15Fiscal year: FY2021Digital Object Identifier: Date added to catalog: 2021-06-07
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Journal Article MedStar Authors Catalog Article 33859359 Available 33859359

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 x 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 x 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 x 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.

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