Exome-wide association study of plasma lipids in >300,000 individuals.

Nat Genet
Authors
Dajiang Liu
Gina Peloso
Haojie Yu
Adam Butterworth
Xiao Wang
Anubha Mahajan
Danish Saleheen
Connor Emdin
Dewan Alam
Alexessander Alves
Philippe Amouyel
Emanuele Di Angelantonio
Dominique Arveiler
Themistocles Assimes
Paul Auer
Usman Baber
Christie Ballantyne
Lia Bang
Marianne Benn
Joshua Bis
Michael Boehnke
Eric Boerwinkle
Jette Bork-Jensen
Erwin Bottinger
Ivan Brandslund
Morris Brown
Fabio Busonero
Mark Caulfield
John Chambers
Daniel Chasman
Y Eugene Chen
Yii-Der Chen
Rajiv Chowdhury
Cramer Christensen
Audrey Chu
John Connell
Francesco Cucca
L Adrienne Cupples
Scott Damrauer
Gail Davies
Ian Deary
George Dedoussis
Joshua Denny
Anna Dominiczak
Marie-Pierre Dube
Tapani Ebeling
Gudny Eiriksdottir
Tõnu Esko
Aliki-Eleni Farmaki
Mary Feitosa
Marco Ferrario
Jean Ferrières
Ian Ford
Myriam Fornage
Paul Franks
Timothy Frayling
Ruth Frikke-Schmidt
Lars Fritsche
Philippe Frossard
Valentin Fuster
Santhi Ganesh
Wei Gao
Melissa Garcia
Christian Gieger
Franco Giulianini
Mark Goodarzi
Harald Grallert
Niels Grarup
Leif Groop
Megan Grove
Vilmundur Gudnason
Torben Hansen
Tamara Harris
Caroline Hayward
Joel Hirschhorn
Oddgeir Holmen
Jennifer Huffman
Yong Huo
Kristian Hveem
Sehrish Jabeen
Anne Jackson
Johanna Jakobsdottir
Marjo-Riitta Jarvelin
Gorm Jensen
Marit Jørgensen
J Wouter Jukema
Johanne Justesen
Pia Kamstrup
Stavroula Kanoni
Fredrik Karpe
Frank Kee
Amit Khera
Derek Klarin
Heikki Koistinen
Jaspal Kooner
Charles Kooperberg
Kari Kuulasmaa
Johanna Kuusisto
Markku Laakso
Timo Lakka
Claudia Langenberg
Anne Langsted
Lenore Launer
Torsten Lauritzen
David Liewald
Li Lin
Allan Linneberg
Ruth Loos
Yingchang Lu
Xiangfeng Lu
Reedik Mägi
Anders Malarstig
Ani Manichaikul
Alisa Manning
Pekka Mäntyselkä
Eirini Marouli
Nicholas Masca
Andrea Maschio
James Meigs
Olle Melander
Andres Metspalu
Andrew Morris
Alanna Morrison
Antonella Mulas
Martina Müller-Nurasyid
Patricia Munroe
Matt Neville
Jonas Nielsen
Sune Nielsen
Børge Nordestgaard
Jose Ordovas
Roxana Mehran
Christoper O'Donnell
Marju Orho-Melander
Cliona Molony
Pieter Muntendam
Sandosh Padmanabhan
Colin Palmer
Dorota Pasko
Aniruddh Patel
Oluf Pedersen
Markus Perola
Annette Peters
Charlotta Pisinger
Giorgio Pistis
Ozren Polasek
Neil Poulter
Bruce Psaty
Daniel Rader
Asif Rasheed
Rainer Rauramaa
Dermot Reilly
Alex Reiner
Frida Renström
Stephen Rich
Paul Ridker
John Rioux
Neil Robertson
Dan Roden
Jerome Rotter
Igor Rudan
Veikko Salomaa
Nilesh Samani
Serena Sanna
Naveed Sattar
Ellen Schmidt
Robert Scott
Peter Sever
Raquel Sevilla
Christian Shaffer
Xueling Sim
Suthesh Sivapalaratnam
Kerrin Small
Albert Smith
Blair Smith
Sangeetha Somayajula
Lorraine Southam
Timothy Spector
Elizabeth Speliotes
John Starr
Kathleen Stirrups
Nathan Stitziel
Konstantin Strauch
Heather Stringham
Praveen Surendran
Hayato Tada
Alan Tall
Hua Tang
Jean-Claude Tardif
Kent Taylor
Stella Trompet
Philip Tsao
Jaakko Tuomilehto
Anne Tybjaerg-Hansen
Natalie van Zuydam
Anette Varbo
Tibor Varga
Jarmo Virtamo
Melanie Waldenberger
Nan Wang
Nick Wareham
Helen Warren
Peter Weeke
Joshua Weinstock
Jennifer Wessel
James Wilson
Peter Wilson
Ming Xu
Hanieh Yaghootkar
Robin Young
Eleftheria Zeggini
He Zhang
Neil Zheng
Weihua Zhang
Yan Zhang
Wei Zhou
Yanhua Zhou
Magdalena Zoledziewska
Charge Diabetes Working Group
EPIC-InterAct Consortium
EPIC-CVD Consortium
GOLD Consortium
VA Million Veteran Program
Joanna Howson
John Danesh
Mark McCarthy
Chad Cowan
Goncalo Abecasis
Panos Deloukas
Kiran Musunuru
Cristen Willer
Sekar Kathiresan
Keywords
Humans
Genetic Predisposition to Disease
Phenotype
Genotype
Risk Factors
Genetic Variation
Genetic Association Studies
Exome
Diabetes Mellitus, Type 2
Coronary Artery Disease
Lipids
Macular Degeneration
Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
Year of Publication
2017
Journal
Nat Genet
Volume
49
Issue
12
Pages
1758-1766
Date Published
2017 Dec
ISSN
1546-1718
DOI
10.1038/ng.3977
PubMed ID
29083408
PubMed Central ID
PMC5709146
Links
Grant list
KL2 TR001100 / TR / NCATS NIH HHS / United States
G9521010 / Medical Research Council / United Kingdom
R01 DK106621 / DK / NIDDK NIH HHS / United States
R01 HL109946 / HL / NHLBI NIH HHS / United States
R01 HL122684 / HL / NHLBI NIH HHS / United States
R21 DA040177 / DA / NIDA NIH HHS / United States
RG/08/014/24067 / British Heart Foundation / United Kingdom
R01 HL118567 / HL / NHLBI NIH HHS / United States
T32 HG000040 / HG / NHGRI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
R01 HL117491 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / Medical Research Council / United Kingdom
MR/L003120/1 / Medical Research Council / United Kingdom
S10 OD018522 / OD / NIH HHS / United States
MC_UU_12015/1 / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL129778 / HL / NHLBI NIH HHS / United States
K99 HL094535 / HL / NHLBI NIH HHS / United States
K01 HL125751 / HL / NHLBI NIH HHS / United States
MR/N005813/1 / Medical Research Council / United Kingdom
R01 HG008983 / HG / NHGRI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
R00 HL094535 / HL / NHLBI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
MC_PC_U127561128 / Medical Research Council / United Kingdom
UM1 CA182913 / CA / NCI NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 DA037904 / DA / NIDA NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
MR/K006584/1 / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
RG/14/5/30893 / British Heart Foundation / United Kingdom
Wellcome Trust / United Kingdom
UL1 TR001881 / TR / NCATS NIH HHS / United States
G0601261 / Medical Research Council / United Kingdom
G0600237 / Medical Research Council / United Kingdom
U54 GM115428 / GM / NIGMS NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States

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