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
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
Jennifer Huffman
- Function : Author
Solomon Musani
- Function : Author
Changwei Li
- Function : Author
Melissa Richard
- Function : Author
Raymond Noordam
- Function : Author
Hugues Aschard
- Function : Author
- PersonId : 1071662
- ORCID : 0000-0002-7554-6783
- IdRef : 139628924
Traci Bartz
- Function : Author
Lawrence Bielak
- Function : Author
Xuan Deng
- Function : Author
Rajkumar Dorajoo
- Function : Author
- PersonId : 786095
- ORCID : 0000-0001-6608-2051
Kurt Lohman
- Function : Author
Alisa Manning
- Function : Author
Tuomo Rankinen
- Function : Author
Albert Smith
- Function : Author
Salman Tajuddin
- Function : Author
Evangelos Evangelou
- Function : Author
Maris Alver
- Function : Author
Xu Chen
- Function : Author
Jasmin Divers
- Function : Author
Ilaria Gandin
- Function : Author
Chuan Gao
- Function : Author
Anuj Goel
- Function : Author
Yanick Hagemeijer
- Function : Author
Sarah Harris
- Function : Author
- PersonId : 800076
- ORCID : 0000-0002-2812-1651
Fernando Hartwig
- Function : Author
Meian He
- Function : Author
Andrea Horimoto
- Function : Author
Fang-Chi Hsu
- Function : Author
Anne Jackson
- Function : Author
Anuradhani Kasturiratne
- Function : Author
Pirjo Komulainen
- Function : Author
Brigitte Kühnel
- Function : Author
Federica Laguzzi
- Function : Author
Joseph Lee
- Function : Author
Jian'An Luan
- Function : Author
Leo-Pekka Lyytikäinen
- Function : Author
Nana Matoba
- Function : Author
Ilja Nolte
- Function : Author
Maik Pietzner
- Function : Author
Muhammad Riaz
- Function : Author
M Abdullah Said
- Function : Author
Robert Scott
- Function : Author
Tamar Sofer
- Function : Author
Alena Stančáková
- Function : Author
Fumihiko Takeuchi
- Function : Author
Bamidele Tayo
- Function : Author
Peter van Der Most
- Function : Author
Tibor Varga
- Function : Author
- PersonId : 801140
- ORCID : 0000-0002-2383-699X
Erin Ware
- Function : Author
Wanqing Wen
- Function : Author
Lisa Yanek
- Function : Author
Weihua Zhang
- Function : Author
Jing Hua Zhao
- Function : Author
Saima Afaq
- Function : Author
Marzyeh Amini
- Function : Author
Dan Arking
- Function : Author
Christie Ballantyne
- Function : Author
Eric Boerwinkle
- Function : Author
Ulrich Broeckel
- Function : Author
Archie Campbell
- Function : Author
Mickaël Canouil
- Function : Author
- PersonId : 781235
- ORCID : 0000-0002-3396-4549
- IdRef : 224973177
John Connell
- Function : Author
Ulf de Faire
- Function : Author
Renée de Mutsert
- Function : Author
H Janaka de Silva
- Function : Author
Jingzhong Ding
- Function : Author
Anna Dominiczak
- Function : Author
Qing Duan
- Function : Author
Charles Eaton
- Function : Author
Ruben Eppinga
- Function : Author
Jessica Faul
- Function : Author
Virginia Fisher
- Function : Author
Terrence Forrester
- Function : Author
Yechiel Friedlander
- Function : Author
Franco Giulianini
- Function : Author
Hans Grabe
- Function : Author
Tamara Harris
- Function : Author
Sami Heikkinen
- Function : Author
Chew-Kiat Heng
- Function : Author
Makoto Hirata
- Function : Author
James Hixson
- Function : Author
Barbara Howard
- Function : Author
David Jacobs
- Function : Author
Craig Johnson
- Function : Author
Jost Bruno Jonas
- Function : Author
Candace Kammerer
- Function : Author
Tomohiro Katsuya
- Function : Author
Chiea Chuen Khor
- Function : Author
- PersonId : 794004
- ORCID : 0000-0002-1128-4729
Tuomas Kilpeläinen
- Function : Author
Heikki Koistinen
- Function : Author
Ivana Kolcic
- Function : Author
Charles Kooperberg
- Function : Author
Jose Krieger
- Function : Author
Steve Kritchevsky
- Function : Author
Michiaki Kubo
- Function : Author
Johanna Kuusisto
- Function : Author
Timo Lakka
- Function : Author
Carl Langefeld
- Function : Author
Claudia Langenberg
- Function : Author
Lenore Launer
- Function : Author
Benjamin Lehne
- Function : Author
Rozenn Lemaitre
- Function : Author
Jingjing Liang
- Function : Author
- PersonId : 801651
- ORCID : 0000-0001-9439-9320
Jianjun Liu
- Function : Author
- PersonId : 764292
- ORCID : 0000-0002-3255-3019
Kiang Liu
- Function : Author
Marie Loh
- Function : Author
Tin Louie
- Function : Author
Reedik Mägi
- Function : Author
Ani Manichaikul
- Function : Author
Colin Mckenzie
- Function : Author
Thomas Meitinger
- Function : Author
Andres Metspalu
- Function : Author
Yuri Milaneschi
- Function : Author
Lili Milani
- Function : Author
Karen Mohlke
- Function : Author
Thomas Mosley
- Function : Author
Kenneth Mukamal
- Function : Author
Mike Nalls
- Function : Author
Matthias Nauck
- Function : Author
Christopher Nelson
- Function : Author
Nona Sotoodehnia
- Function : Author
Jeff O'Connell
- Function : Author
Nicholette Palmer
- Function : Author
Raha Pazoki
- Function : Author
Nancy Pedersen
- Function : Author
Annette Peters
- Function : Author
- PersonId : 764072
- ORCID : 0000-0001-6645-0985
Patricia Peyser
- Function : Author
Ozren Polasek
- Function : Author
Neil Poulter
- Function : Author
Leslie Raffel
- Function : Author
Olli Raitakari
- Function : Author
Alex Reiner
- Function : Author
Stephen Rich
- Function : Author
Antonietta Robino
- Function : Author
Jennifer Robinson
- Function : Author
Lynda Rose
- Function : Author
Igor Rudan
- Function : Author
Carsten Schmidt
- Function : Author
Pamela Schreiner
- Function : Author
William Scott
- Function : Author
Peter Sever
- Function : Author
- PersonId : 807495
- ORCID : 0000-0003-0421-2409
Stephen Sidney
- Function : Author
Mario Sims
- Function : Author
Blair Smith
- Function : Author
Jennifer Smith
- Function : Author
Harold Snieder
- Function : Author
John Starr
- Function : Author
Konstantin Strauch
- Function : Author
Diana van Heemst
- Function : Author
Dragana Vuckovic
- Function : Author
Melanie Waldenberger
- Function : Author
Yujie Wang
- Function : Author
Wen Bin Wei
- Function : Author
Gregory Wilson
- Function : Author
Bing Yu
- Function : Author
- PersonId : 765545
- ORCID : 0000-0001-7752-592X
Caizheng Yu
- Function : Author
Jian-Min Yuan
- Function : Author
Wei Zhao
- Function : Author
Alan Zonderman
- Function : Author
Diane Becker
- Function : Author
Michael Boehnke
- Function : Author
Donald Bowden
- Function : Author
John Chambers
- Function : Author
Ian Deary
- Function : Author
Tõnu Esko
- Function : Author
Martin Farrall
- Function : Author
Paul Franks
- Function : Author
Barry Freedman
- Function : Author
Paolo Gasparini
- Function : Author
Christian Gieger
- Function : Author
Bernardo Horta
- Function : Author
Yoichiro Kamatani
- Function : Author
Norihiro Kato
- Function : Author
Jaspal Kooner
- Function : Author
Markku Laakso
- Function : Author
Karin Leander
- Function : Author
- PersonId : 773564
- ORCID : 0000-0002-1404-9222
Terho Lehtimäki
- Function : Author
Patrik Magnusson
- Function : Author
Brenda Penninx
- Function : Author
Alexandre Pereira
- Function : Author
- PersonId : 761027
- ORCID : 0000-0002-7243-4807
Rainer Rauramaa
- Function : Author
Nilesh Samani
- Function : Author
- PersonId : 802419
- ORCID : 0000-0002-3286-8133
James Scott
- Function : Author
- PersonId : 766233
- ORCID : 0000-0002-2263-7024
Xiao-Ou Shu
- Function : Author
Pim van Der Harst
- Function : Author
Lynne Wagenknecht
- Function : Author
Ya Xing Wang
- Function : Author
Nicholas Wareham
- Function : Author
Hugh Watkins
- Function : Author
David Weir
- Function : Author
Ananda Wickremasinghe
- Function : Author
Wei Zheng
- Function : Author
- PersonId : 756070
- ORCID : 0000-0003-1226-070X
Paul Elliott
- Function : Author
- PersonId : 764774
- ORCID : 0000-0003-1570-3289
Claude Bouchard
- Function : Author
Michele Evans
- Function : Author
Vilmundur Gudnason
- Function : Author
Ching-Ti Liu
- Function : Author
Yongmei Liu
- Function : Author
Bruce Psaty
- Function : Author
Paul Ridker
- Function : Author
Sharon Kardia
- Function : Author
Xiaofeng Zhu
- Function : Author
Dennis Mook-Kanamori
- Function : Author
Tanika Kelly
- Function : Author
Ervin Fox
- Function : Author
Caroline Hayward
- Function : Author
Jingmin Liu
- Function : Author
W James Gauderman
- Function : Author
Kenneth Rice
- Function : Author
Daniel Chasman
- Function : Author
L Adrienne Cupples
- Function : Author
Abstract
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.