A Large-Scale Genome-Wide Gene-Sleep Interaction Study in 732,564 Participants Identifies Lipid Loci Explaining Sleep-Associated Lipid Disturbances
Authors: 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 ,   Million Veteran Program, 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 
Published: September 2024

We 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.