Author:
Noordam Raymond,Wang Wenyi,Nagarajan Pavithra,Wang Heming,Brown Michael R,Bentley Amy R,Hui Qin,Kraja Aldi T,Morrison John L,O’Connel Jeffrey R,Lee Songmi,Schwander Karen,Bartz Traci M,de las Fuentes Lisa,Feitosa Mary F,Guo Xiuqing,Hanfei Xu,Harris Sarah E,Huang Zhijie,Kals Mart,Lefevre Christophe,Mangino Massimo,Milaneschi Yuri,van der Most Peter,Pacheco Natasha L,Palmer Nicholette D,Rao Varun,Rauramaa Rainer,Sun Quan,Tabara Yasuharu,Vojinovic Dina,Wang Yujie,Weiss Stefan,Yang Qian,Zhao Wei,Zhu Wanying,Abu Yusuf Ansari Md,Aschard Hugues,Anugu Pramod,Assimes Themistocles L,Attia John,Baker Laura D,Ballantyne Christie,Bazzano Lydia,Boerwinkle Eric,Cade Brain,Chen Hung-hsin,Chen Wei,Ida Chen Yii-Der,Chen Zekai,Cho Kelly,De Anda-Duran Ileana,Dimitrov Latchezar,Do Anh,Edwards Todd,Faquih Tariq,Hingorani Aroon,Fisher-Hoch Susan P,Gaziano J. Michael,Gharib Sina A,Giri Ayush,Ghanbari Mohsen,Grabe Hans Jörgen,Graff Mariaelisa,Gu C Charles,He Jiang,Heikkinen Sami,Hixson James,Ho Yuk-Lam,Hood Michelle M,Houghton Serena C,Karvonen-Gutierrez Carrie A,Kawaguchi Takahisa,Kilpeläinen Tuomas O,Komulainen Pirjo,Lin Henry J,Linchangco Gregorio V,Luik Annemarie I,Ma Jintao,Meigs James B,McCormick Joseph B,Menni Cristina,Nolte Ilja M,Norris Jill M,Petty Lauren E,Polikowsky Hannah G,Raffield Laura M,Rich Stephen S,Riha Renata L,Russ Thomas C,Ruiz-Narvaez Edward A,Sitlani Colleen M,Smith Jennifer A,Snieder Harold,Sofer Tamar,Shen Botong,Tang Jingxian,Taylor Kent D,Teder-Laving Maris,Triatin Rima,Tsai Michael Y,Völzke Henry,Westerman Kenneth E.,Xia Rui,Yao Jie,Young Kristin L,Zhang Ruiyuan,Zonderman Alan B,Zhu Xiaofeng,Below Jennifer E,Cox Simon R,Evans Michelle,Fornage Myriam,Fox Ervin R,Franceschini Nora,Harlow Sioban D,Holliday Elizabeth,Ikram M. Arfan,Kelly Tanika,Lakka Timo A,Lawlor Deborah A,Li Changwei,Liu Ching-Ti,Mägi Reedik,Manning Alisa K,Matsuda Fumihiko,Morrison Alanna C,Nauck Matthias,North Kari E,Penninx Brenda WJH,Province Michael A,Psaty Bruce M,Rotter Jerome I,Spector Tim D,Wagenknecht Lynne E,Willems van Dijk Ko,Study Lifelines Cohort, ,Jaquish Cashell E,Wilson Peter WF,Peyser Patricia A,Munroe Patricia B,de Vries Paul S,Gauderman W James,Sun Yan V,Chen Han,Miller Clint L,Winkler Thomas W,Rao Dabeeru C,Redline Susan,van Heemst Diana
Abstract
AbstractWe performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for the one-degree of freedom tests of interaction and two-degree of freedom joint tests of the main and interaction effect. In the cross-population meta-analyses, the one-degree of freedom variant-sleep interaction test identified 10 loci (Pint<5.0e-9) not previously observed for lipids. Of interest, theASPHlocus (TG, LTST) is a target for aspartic and succinic acid metabolism previously shown to improve sleep and cardiovascular risk. The two-degree of freedom analyses identified an additional 7 loci that showed evidence for variant-sleep interaction (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Of these, theSLC8A1locus (TG, STST) has been considered a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the 17 (9 with STST; 8 with LTST) loci identified in this large-scale initiative provides evidence into the biomolecular mechanisms underpinning sleep-duration-associated changes in lipid levels. The identified druggable targets may contribute to the development of novel therapies for dyslipidemia in people with sleep disturbances.