Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
Authors: Kilpeläinen Tuomas O. , Bentley Amy R. , Noordam Raymond , Sung Yun Ju , Schwander Karen , Winkler Thomas W. , Jakupović Hermina , Chasman Daniel I. , Manning Alisa , Ntalla Ioanna , Aschard Hugues , Brown Michael R. , de las Fuentes Lisa , Franceschini Nora , Guo Xiuqing , Vojinovic Dina , Aslibekyan Stella , Feitosa Mary F. , Kho Minjung , Musani Solomon K. , Richard Melissa , Wang Heming , Wang Zhe , Bartz Traci M. , Bielak Lawrence F. , Campbell Archie , Dorajoo Rajkumar , Fisher Virginia , Hartwig Fernando P. , Horimoto Andrea R. V. R. , Li Changwei , Lohman Kurt K. , Marten Jonathan , Sim Xueling , Smith Albert V. , Tajuddin Salman M. , Alver Maris , Amini Marzyeh , Boissel Mathilde , Chai Jin Fang , Chen Xu , Divers Jasmin , Evangelou Evangelos , Gao Chuan , Graff Mariaelisa , Harris Sarah E. , He Meian , Hsu Fang-Chi , Jackson Anne U. , Zhao Jing Hua , Kraja Aldi T. , Kühnel Brigitte , Laguzzi Federica , Lyytikäinen Leo-Pekka , Nolte Ilja M. , Rauramaa Rainer , Riaz Muhammad , Robino Antonietta , Rueedi Rico , Stringham Heather M. , Takeuchi Fumihiko , van der Most Peter J. , Varga Tibor V. , Verweij Niek , Ware Erin B. , Wen Wanqing , Li Xiaoyin , Yanek Lisa R. , Amin Najaf , Arnett Donna K. , Boerwinkle Eric , Brumat Marco , Cade Brian , Canouil Mickaël , Chen Yii-Der Ida , Concas Maria Pina , Connell John , de Mutsert Renée , de Silva H. Janaka , de Vries Paul S. , Demirkan Ayşe , Ding Jingzhong , Eaton Charles B. , Faul Jessica D. , Friedlander Yechiel , Gabriel Kelley P. , Ghanbari Mohsen , Giulianini Franco , Gu Chi Charles , Gu Dongfeng , Harris Tamara B. , He Jiang , Heikkinen Sami , Heng Chew-Kiat , Hunt Steven C. , Ikram M. Arfan , Jonas Jost B. , Koh Woon-Puay , Komulainen Pirjo , Krieger Jose E. , Kritchevsky Stephen B. , Kutalik Zoltán , Kuusisto Johanna , Langefeld Carl D. , Langenberg Claudia , Launer Lenore J. , Leander Karin , Lemaitre Rozenn N. , Lewis Cora E. , Liang Jingjing ,   Lifelines Cohort Study, Alizadeh Behrooz Z. , Boezen H. Marike , Franke Lude , Navis Gerjan , Rots Marianne , Swertz Morris , Wolffenbuttel Bruce H. R. , Wijmenga Cisca , Liu Jianjun , Mägi Reedik , Manichaikul Ani , Meitinger Thomas , Metspalu Andres , Milaneschi Yuri , Mohlke Karen L. , Mosley Thomas H. , Murray Alison D. , Nalls Mike A. , Nang Ei-Ei Khaing , Nelson Christopher P. , Nona Sotoodehnia , Norris Jill M. , Nwuba Chiamaka Vivian , O’Connell Jeff , Palmer Nicholette D. , Papanicolau George J. , Pazoki Raha , Pedersen Nancy L. , Peters Annette , Peyser Patricia A. , Polasek Ozren , Porteous David J. , Poveda Alaitz , Raitakari Olli T. , Rich Stephen S. , Risch Neil , Robinson Jennifer G. , Rose Lynda M. , Rudan Igor , Schreiner Pamela J. , Scott Robert A. , Sidney Stephen S. , Sims Mario , Smith Jennifer A. , Snieder Harold , Sofer Tamar , Starr John M. , Sternfeld Barbara , Strauch Konstantin , Tang Hua , Taylor Kent D. , Tsai Michael Y. , Tuomilehto Jaakko , Uitterlinden André G. , van der Ende M. Yldau , van Heemst Diana , Voortman Trudy , Waldenberger Melanie , Wennberg Patrik , Wilson Gregory , Xiang Yong-Bing , Yao Jie , Yu Caizheng , Yuan Jian-Min , Zhao Wei , Zonderman Alan B. , Becker Diane M. , Boehnke Michael , Bowden Donald W. , de Faire Ulf , Deary Ian J. , Elliott Paul , Esko Tõnu , Freedman Barry I. , Froguel Philippe , Gasparini Paolo , Gieger Christian , Kato Norihiro , Laakso Markku , Lakka Timo A. , Lehtimäki Terho , Magnusson Patrik K. E. , Oldehinkel Albertine J. , Penninx Brenda W. J. H. , Samani Nilesh J. , Shu Xiao-Ou , van der Harst Pim , Van Vliet-Ostaptchouk Jana V. , Vollenweider Peter , Wagenknecht Lynne E. , Wang Ya X. , Wareham Nicholas J. , Weir David R. , Wu Tangchun , Zheng Wei , Zhu Xiaofeng , Evans Michele K. , Franks Paul W. , Gudnason Vilmundur , Hayward Caroline , Horta Bernardo L. , Kelly Tanika N. , Liu Yongmei , North Kari E. , Pereira Alexandre C. , Ridker Paul M. , Tai E. Shyong , van Dam Rob M. , Fox Ervin R. , Kardia Sharon L. R. , Liu Ching-Ti , Mook-Kanamori Dennis O. , Province Michael A. , Redline Susan , van Duijn Cornelia M. , Rotter Jerome I. , Kooperberg Charles B. , Gauderman W. James , Psaty Bruce M. , Rice Kenneth , Munroe Patricia B. , Fornage Myriam , Cupples L. Adrienne , Rotimi Charles N. , Morrison Alanna C. , Rao Dabeeru C. , Loos Ruth J. F. 
Published: January 2019

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.