Biological, clinical and population relevance of 95 loci for blood lipids.

Nature
Authors
Tanya Teslovich
Kiran Musunuru
Albert Smith
Andrew Edmondson
Ioannis Stylianou
Masahiro Koseki
James Pirruccello
Samuli Ripatti
Daniel Chasman
Cristen Willer
Christopher Johansen
Sigrid Fouchier
Aaron Isaacs
Gina Peloso
Maja Barbalic
Sally Ricketts
Joshua Bis
Yurii Aulchenko
Gudmar Thorleifsson
Mary Feitosa
John Chambers
Marju Orho-Melander
Olle Melander
Toby Johnson
Xiaohui Li
Xiuqing Guo
Mingyao Li
Yoon Cho
Min Go
Young Kim
Jong-Young Lee
Taesung Park
Kyunga Kim
Xueling Sim
Rick Ong
Damien Croteau-Chonka
Leslie Lange
Joshua Smith
Kijoung Song
Jing Zhao
Xin Yuan
Jian'an Luan
Claudia Lamina
Andreas Ziegler
Weihua Zhang
Robert Zee
Alan Wright
Jacqueline Witteman
James Wilson
Gonneke Willemsen
H-Erich Wichmann
John Whitfield
Dawn Waterworth
Nicholas Wareham
Gérard Waeber
Peter Vollenweider
Benjamin Voight
Veronique Vitart
André Uitterlinden
Manuela Uda
Jaakko Tuomilehto
John Thompson
Toshiko Tanaka
Ida Surakka
Heather Stringham
Tim Spector
Nicole Soranzo
Johannes Smit
Juha Sinisalo
Kaisa Silander
Eric Sijbrands
Angelo Scuteri
James Scott
David Schlessinger
Serena Sanna
Veikko Salomaa
Juha Saharinen
Chiara Sabatti
Aimo Ruokonen
Igor Rudan
Lynda Rose
Robert Roberts
Mark Rieder
Bruce Psaty
Peter Pramstaller
Irene Pichler
Markus Perola
Brenda Penninx
Nancy Pedersen
Cristian Pattaro
Alex Parker
Guillaume Pare
Ben Oostra
Christopher O'Donnell
Markku Nieminen
Deborah Nickerson
Grant Montgomery
Thomas Meitinger
Ruth McPherson
Mark McCarthy
Wendy McArdle
David Masson
Nicholas Martin
Fabio Marroni
Massimo Mangino
Patrik Magnusson
Gavin Lucas
Robert Luben
Ruth Loos
Marja-Liisa Lokki
Guillaume Lettre
Claudia Langenberg
Lenore Launer
Edward Lakatta
Reijo Laaksonen
Kirsten Kyvik
Florian Kronenberg
Inke König
Kay-Tee Khaw
Jaakko Kaprio
Lee Kaplan
Asa Johansson
Marjo-Riitta Jarvelin
A Cecile Janssens
Erik Ingelsson
Wilmar Igl
G Kees Hovingh
Jouke-Jan Hottenga
Albert Hofman
Andrew Hicks
Christian Hengstenberg
Iris Heid
Caroline Hayward
Aki Havulinna
Nicholas Hastie
Tamara Harris
Talin Haritunians
Alistair Hall
Ulf Gyllensten
Candace Guiducci
Leif Groop
Elena Gonzalez
Christian Gieger
Nelson Freimer
Luigi Ferrucci
Jeanette Erdmann
Paul Elliott
Kenechi Ejebe
Angela Döring
Anna Dominiczak
Serkalem Demissie
Panagiotis Deloukas
Eco De Geus
Ulf de Faire
Gabriel Crawford
Francis Collins
Yii-Der Chen
Mark Caulfield
Harry Campbell
Noel Burtt
Lori Bonnycastle
Dorret Boomsma
S Matthijs Boekholdt
Richard Bergman
Inês Barroso
Stefania Bandinelli
Christie Ballantyne
Themistocles Assimes
Thomas Quertermous
David Altshuler
Mark Seielstad
Tien Wong
E-Shyong Tai
Alan Feranil
Christopher Kuzawa
Linda Adair
Herman Taylor
Ingrid Borecki
Stacey Gabriel
James Wilson
Hilma Holm
Unnur Thorsteinsdottir
Vilmundur Gudnason
Ronald Krauss
Karen Mohlke
Jose Ordovas
Patricia Munroe
Jaspal Kooner
Alan Tall
Robert Hegele
John Kastelein
Eric Schadt
Jerome Rotter
Eric Boerwinkle
David Strachan
Vincent Mooser
Kari Stefansson
Muredach Reilly
Nilesh Samani
Heribert Schunkert
L Adrienne Cupples
Manjinder Sandhu
Paul Ridker
Daniel Rader
Cornelia van Duijn
Leena Peltonen
Gonçalo Abecasis
Michael Boehnke
Sekar Kathiresan
Keywords
Animals
Female
Humans
Male
Mice
Phenotype
Genotype
Reproducibility of Results
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Cholesterol, HDL
Cholesterol, LDL
Triglycerides
European Continental Ancestry Group
Genetic Loci
Lipid Metabolism
Asian Continental Ancestry Group
Liver
Coronary Artery Disease
Europe
African Americans
Lipids
N-Acetylgalactosaminyltransferases
Protein Phosphatase 1
Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Year of Publication
2010
Journal
Nature
Volume
466
Issue
7307
Pages
707-13
Date Published
2010 Aug 5
ISSN
1476-4687
DOI
10.1038/nature09270
PubMed ID
20686565
PubMed Central ID
PMC3039276
Links
Grant list
068545/Z/02 / Wellcome Trust / United Kingdom
076113/B/04/Z / Wellcome Trust / United Kingdom
077016/Z/05/Z / Wellcome Trust / United Kingdom
079895 / Wellcome Trust / United Kingdom
1Z01 HG000024 / HG / NHGRI NIH HHS / United States
5R01DK06833603 / DK / NIDDK NIH HHS / United States
5R01DK07568102 / DK / NIDDK NIH HHS / United States
5R01HL087679-02 / HL / NHLBI NIH HHS / United States
5R01HL08770003 / HL / NHLBI NIH HHS / United States
5R01HL08821502 / HL / NHLBI NIH HHS / United States
CA 047988 / CA / NCI NIH HHS / United States
CZB/4/710 / Chief Scientist Office / United Kingdom
DK062370 / DK / NIDDK NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
DK072193 / DK / NIDDK NIH HHS / United States
DK078150 / DK / NIDDK NIH HHS / United States
DK56350 / DK / NIDDK NIH HHS / United States
ES10126 / ES / NIEHS NIH HHS / United States
G0000934 / Medical Research Council / United Kingdom
G0401527 / Medical Research Council / United Kingdom
G0601966 / Medical Research Council / United Kingdom
G0700931 / Medical Research Council / United Kingdom
G0701863 / Medical Research Council / United Kingdom
G0801056 / Medical Research Council / United Kingdom
G0801566 / Medical Research Council / United Kingdom
G9521010 / Medical Research Council / United Kingdom
G9521010D / Medical Research Council / United Kingdom
HHSN268200625226C / PHS HHS / United States
HL 04381 / HL / NHLBI NIH HHS / United States
HL 080467 / HL / NHLBI NIH HHS / United States
HL-54776 / HL / NHLBI NIH HHS / United States
HL085144 / HL / NHLBI NIH HHS / United States
K99 HL098364 / HL / NHLBI NIH HHS / United States
K99 HL098364 / HL / NHLBI NIH HHS / United States
K99 HL098364-01 / HL / NHLBI NIH HHS / United States
K99HL094535 / HL / NHLBI NIH HHS / United States
M01-RR00425 / RR / NCRR NIH HHS / United States
MC_QA137934 / Medical Research Council / United Kingdom
MC_U106179471 / Medical Research Council / United Kingdom
MC_U106188470 / Medical Research Council / United Kingdom
MC_U127561128 / Medical Research Council / United Kingdom
N01 HC-15103 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
N01-HC-85084 / HC / NHLBI NIH HHS / United States
N01-HC-85085 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01-HG-65403 / HG / NHGRI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
PG/02/128 / British Heart Foundation / United Kingdom
PG/08/094 / British Heart Foundation / United Kingdom
PG/08/094/26019 / British Heart Foundation / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 DK078150 / DK / NIDDK NIH HHS / United States
R01 HL087647 / HL / NHLBI NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
R01 HL089650 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
R01HL087652 / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
R24 HD050924 / HD / NICHD NIH HHS / United States
RC1 HL099634 / HL / NHLBI NIH HHS / United States
RC1 HL099634 / HL / NHLBI NIH HHS / United States
RC1 HL099634-02 / HL / NHLBI NIH HHS / United States
RC1 HL099793 / HL / NHLBI NIH HHS / United States
RC2 HL101864, / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
RG/07/005/23633 / British Heart Foundation / United Kingdom
RR20649 / RR / NCRR NIH HHS / United States
SP/08/005/25115 / British Heart Foundation / United Kingdom
T32 GM007092 / GM / NIGMS NIH HHS / United States
T32 HG00040 / HG / NHGRI NIH HHS / United States
T32HL007208 / HL / NHLBI NIH HHS / United States
TW05596 / TW / FIC NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
U01 HL069757 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
U54 RR020278 / RR / NCRR NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
Intramural NIH HHS / United States

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