Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Paul de Vries (1) , Michael Brown (1) , Amy Bentley (2) , Yun Sung (1, 3) , Thomas Winkler (4) , Ioanna Ntalla (5) , Karen Schwander (6) , Aldi Kraja (3) , Xiuqing Guo (7) , Nora Franceschini (8) , Ching-Yu Cheng (9, 10) , Xueling Sim (10) , Dina Vojinovic (11) , Jennifer Huffman , Solomon Musani , Changwei Li , Mary Feitosa (3) , Melissa Richard , Raymond Noordam , Hugues Aschard (12) , Traci Bartz , Lawrence Bielak , Xuan Deng , Rajkumar Dorajoo , Kurt Lohman , Alisa Manning , Tuomo Rankinen , Albert Smith , Salman Tajuddin , Evangelos Evangelou , Mariaelisa Graff (8) , Maris Alver , Mathilde Boissel (13) , Jin Fang Chai (10) , Xu Chen , Jasmin Divers , Ilaria Gandin , Chuan Gao , Anuj Goel , Yanick Hagemeijer , Sarah Harris , Fernando Hartwig , Meian He , Andrea Horimoto , Fang-Chi Hsu , Anne Jackson , Anuradhani Kasturiratne , Pirjo Komulainen , Brigitte Kühnel , Federica Laguzzi , Joseph Lee , Jian'An Luan , Leo-Pekka Lyytikäinen , Nana Matoba , Ilja Nolte , Maik Pietzner , Muhammad Riaz , M Abdullah Said , Robert Scott , Tamar Sofer , Alena Stančáková , Fumihiko Takeuchi , Bamidele Tayo , Peter van Der Most , Tibor Varga , Yajuan Wang (8) , Erin Ware , Wanqing Wen , Lisa Yanek , Weihua Zhang , Jing Hua Zhao , Saima Afaq , Najaf Amin (11) , Marzyeh Amini , Dan Arking , Tin Aung (9) , Christie Ballantyne , Eric Boerwinkle , Ulrich Broeckel , Archie Campbell , Mickaël Canouil (13) , Sabanayagam Charumathi (9) , Yii-Der Ida Chen (7) , John Connell , Ulf de Faire , Lisa de Las Fuentes (3) , Renée de Mutsert , H Janaka de Silva , Jingzhong Ding , Anna Dominiczak , Qing Duan , Charles Eaton , Ruben Eppinga , Jessica Faul , Virginia Fisher , Terrence Forrester , Oscar Franco (11) , Yechiel Friedlander , Mohsen Ghanbari (11) , Franco Giulianini , Hans Grabe , Megan Grove (1) , C Charles Gu (3) , Tamara Harris , Sami Heikkinen , Chew-Kiat Heng , Makoto Hirata , James Hixson , Barbara Howard , M Arfan Ikram (11) , David Jacobs , Craig Johnson , Jost Bruno Jonas , Candace Kammerer , Tomohiro Katsuya , Chiea Chuen Khor , Tuomas Kilpeläinen , Woon-Puay Koh (10) , Heikki Koistinen , Ivana Kolcic , Charles Kooperberg , Jose Krieger , Steve Kritchevsky , Michiaki Kubo , Johanna Kuusisto , Timo Lakka , Carl Langefeld , Claudia Langenberg , Lenore Launer , Benjamin Lehne , Rozenn Lemaitre , Yize Li (3) , Jingjing Liang , Jianjun Liu , Kiang Liu , Marie Loh , Tin Louie , Reedik Mägi , Ani Manichaikul , Colin Mckenzie , Thomas Meitinger , Andres Metspalu , Yuri Milaneschi , Lili Milani , Karen Mohlke , Thomas Mosley , Kenneth Mukamal , Mike Nalls , Matthias Nauck , Christopher Nelson , Nona Sotoodehnia , Jeff O'Connell , Nicholette Palmer , Raha Pazoki , Nancy Pedersen , Annette Peters , Patricia Peyser , Ozren Polasek , Neil Poulter , Leslie Raffel , Olli Raitakari , Alex Reiner , Treva Rice (3) , Stephen Rich , Antonietta Robino , Jennifer Robinson , Lynda Rose , Igor Rudan , Carsten Schmidt , Pamela Schreiner , William Scott , Peter Sever , Yuan Shi (9) , Stephen Sidney , Mario Sims , Blair Smith , Jennifer Smith , Harold Snieder , John Starr , Konstantin Strauch , Nicholas Tan (9) , Kent Taylor (7) , Yik Ying Teo (10) , Yih Chung Tham (9) , André Uitterlinden (11) , Diana van Heemst , Dragana Vuckovic , Melanie Waldenberger , Lihua Wang (3) , Yujie Wang , Zhe Wang (1) , Wen Bin Wei , Christine Williams (3) , Gregory Wilson , Mary Wojczynski (3) , Jie Yao (7) , Bing Yu , Caizheng Yu , Jian-Min Yuan , Wei Zhao , Alan Zonderman , Diane Becker , Michael Boehnke , Donald Bowden , John Chambers , Ian Deary , Tõnu Esko , Martin Farrall , Paul Franks , Barry Freedman , Philippe Froguel (13) , Paolo Gasparini , Christian Gieger , Bernardo Horta , Yoichiro Kamatani , Norihiro Kato , Jaspal Kooner , Markku Laakso , Karin Leander , Terho Lehtimäki , Patrik Magnusson , Brenda Penninx , Alexandre Pereira , Rainer Rauramaa , Nilesh Samani , James Scott , Xiao-Ou Shu , Pim van Der Harst , Lynne Wagenknecht , Ya Xing Wang , Nicholas Wareham , Hugh Watkins , David Weir , Ananda Wickremasinghe , Wei Zheng , Paul Elliott , Kari North (8) , Claude Bouchard , Michele Evans , Vilmundur Gudnason , Ching-Ti Liu , Yongmei Liu , Bruce Psaty , Paul Ridker , Rob van Dam (10) , Sharon Kardia , Xiaofeng Zhu , Charles Rotimi (2) , Dennis Mook-Kanamori , Myriam Fornage (1) , Tanika Kelly , Ervin Fox , Caroline Hayward , Cornelia van Duijn (11) , E Shyong Tai (10) , Tien Yin Wong (9) , Jingmin Liu , Jerome Rotter (7) , W James Gauderman , Michael Province (3) , Patricia Munroe (5) , Kenneth Rice , Daniel Chasman , L Adrienne Cupples , Dabeeru Rao (3) , Alanna Morrison (1)

1 UTHealth - The University of Texas Health Science Center at Houston
2 NIH - National Institutes of Health [Bethesda]
3 WUSTL - Washington University in Saint Louis
4 University of Regensburg
5 QMUL - Queen Mary University of London
6 Washington University School of Medicine in St. Louis
7 Harbor UCLA Medical Center [Torrance, Ca.]
8 UNC - University of North Carolina at Chapel Hill
9 Singapore National Eye Centre and Duke-NUS [Singapore]
10 NUS - National University of Singapore
11 Erasmus MC - Erasmus University Medical Center [Rotterdam]
12 Département de Biologie Computationnelle - Department of Computational Biology
13 Institut Pasteur de Lille

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Keywords: alcohol consumption; cholesterol; gene-environment interactions; gene-lifestyle interactions; genome-wide association studies; lipids; triglycerides

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

Paul de Vries, Michael Brown, Amy Bentley, Yun Sung, Thomas Winkler, et al.. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American Journal of Epidemiology, 2019, 188 (6), pp.1033-1054. ⟨10.1093/aje/kwz005⟩. ⟨pasteur-03278557⟩