Biological, clinical and population relevance of 95 loci for blood lipids.
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.
Teslovich
Tanya M
TM
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Musunuru
Kiran
K
Smith
Albert V
AV
Edmondson
Andrew C
AC
Stylianou
Ioannis M
IM
Koseki
Masahiro
M
Pirruccello
James P
JP
Ripatti
Samuli
S
Chasman
Daniel I
DI
Willer
Cristen J
CJ
Johansen
Christopher T
CT
Fouchier
Sigrid W
SW
Isaacs
Aaron
A
Peloso
Gina M
GM
Barbalic
Maja
M
Ricketts
Sally L
SL
Bis
Joshua C
JC
Aulchenko
Yurii S
YS
Thorleifsson
Gudmar
G
Feitosa
Mary F
MF
Chambers
John
J
Orho-Melander
Marju
M
Melander
Olle
O
Johnson
Toby
T
Li
Xiaohui
X
Guo
Xiuqing
X
Li
Mingyao
M
Shin Cho
Yoon
Y
Jin Go
Min
M
Jin Kim
Young
Y
Lee
Jong-Young
JY
Park
Taesung
T
Kim
Kyunga
K
Sim
Xueling
X
Twee-Hee Ong
Rick
R
Croteau-Chonka
Damien C
DC
Lange
Leslie A
LA
Smith
Joshua D
JD
Song
Kijoung
K
Hua Zhao
Jing
J
Yuan
Xin
X
Luan
Jian'an
J
Lamina
Claudia
C
Ziegler
Andreas
A
Zhang
Weihua
W
Zee
Robert Y L
RY
Wright
Alan F
AF
Witteman
Jacqueline C M
JC
Wilson
James F
JF
Willemsen
Gonneke
G
Wichmann
H-Erich
HE
Whitfield
John B
JB
Waterworth
Dawn M
DM
Wareham
Nicholas J
NJ
Waeber
Gérard
G
Vollenweider
Peter
P
Voight
Benjamin F
BF
Vitart
Veronique
V
Uitterlinden
Andre G
AG
Uda
Manuela
M
Tuomilehto
Jaakko
J
Thompson
John R
JR
Tanaka
Toshiko
T
Surakka
Ida
I
Stringham
Heather M
HM
Spector
Tim D
TD
Soranzo
Nicole
N
Smit
Johannes H
JH
Sinisalo
Juha
J
Silander
Kaisa
K
Sijbrands
Eric J G
EJ
Scuteri
Angelo
A
Scott
James
J
Schlessinger
David
D
Sanna
Serena
S
Salomaa
Veikko
V
Saharinen
Juha
J
Sabatti
Chiara
C
Ruokonen
Aimo
A
Rudan
Igor
I
Rose
Lynda M
LM
Roberts
Robert
R
Rieder
Mark
M
Psaty
Bruce M
BM
Pramstaller
Peter P
PP
Pichler
Irene
I
Perola
Markus
M
Penninx
Brenda W J H
BW
Pedersen
Nancy L
NL
Pattaro
Cristian
C
Parker
Alex N
AN
Pare
Guillaume
G
Oostra
Ben A
BA
O'Donnell
Christopher J
CJ
Nieminen
Markku S
MS
Nickerson
Deborah A
DA
Montgomery
Grant W
GW
Meitinger
Thomas
T
McPherson
Ruth
R
McCarthy
Mark I
MI
McArdle
Wendy
W
Masson
David
D
Martin
Nicholas G
NG
Marroni
Fabio
F
Mangino
Massimo
M
Magnusson
Patrik K E
PK
Lucas
Gavin
G
Luben
Robert
R
Loos
Ruth J F
RJ
Lokki
Marja-Liisa
ML
Lettre
Guillaume
G
Langenberg
Claudia
C
Launer
Lenore J
LJ
Lakatta
Edward G
EG
Laaksonen
Reijo
R
Kyvik
Kirsten O
KO
Kronenberg
Florian
F
König
Inke R
IR
Khaw
Kay-Tee
KT
Kaprio
Jaakko
J
Kaplan
Lee M
LM
Johansson
Asa
A
Jarvelin
Marjo-Riitta
MR
Janssens
A Cecile J W
AC
Ingelsson
Erik
E
Igl
Wilmar
W
Kees Hovingh
G
G
Hottenga
Jouke-Jan
JJ
Hofman
Albert
A
Hicks
Andrew A
AA
Hengstenberg
Christian
C
Heid
Iris M
IM
Hayward
Caroline
C
Havulinna
Aki S
AS
Hastie
Nicholas D
ND
Harris
Tamara B
TB
Haritunians
Talin
T
Hall
Alistair S
AS
Gyllensten
Ulf
U
Guiducci
Candace
C
Groop
Leif C
LC
Gonzalez
Elena
E
Gieger
Christian
C
Freimer
Nelson B
NB
Ferrucci
Luigi
L
Erdmann
Jeanette
J
Elliott
Paul
P
Ejebe
Kenechi G
KG
Döring
Angela
A
Dominiczak
Anna F
AF
Demissie
Serkalem
S
Deloukas
Panagiotis
P
de Geus
Eco J C
EJ
de Faire
Ulf
U
Crawford
Gabriel
G
Collins
Francis S
FS
Chen
Yii-der I
YD
Caulfield
Mark J
MJ
Campbell
Harry
H
Burtt
Noel P
NP
Bonnycastle
Lori L
LL
Boomsma
Dorret I
DI
Boekholdt
S Matthijs
SM
Bergman
Richard N
RN
Barroso
Inês
I
Bandinelli
Stefania
S
Ballantyne
Christie M
CM
Assimes
Themistocles L
TL
Quertermous
Thomas
T
Altshuler
David
D
Seielstad
Mark
M
Wong
Tien Y
TY
Tai
E-Shyong
ES
Feranil
Alan B
AB
Kuzawa
Christopher W
CW
Adair
Linda S
LS
Taylor
Herman A
HA
Borecki
Ingrid B
IB
Gabriel
Stacey B
SB
Wilson
James G
JG
Holm
Hilma
H
Thorsteinsdottir
Unnur
U
Gudnason
Vilmundur
V
Krauss
Ronald M
RM
Mohlke
Karen L
KL
Ordovas
Jose M
JM
Munroe
Patricia B
PB
Kooner
Jaspal S
JS
Tall
Alan R
AR
Hegele
Robert A
RA
Kastelein
John J P
JJ
Schadt
Eric E
EE
Rotter
Jerome I
JI
Boerwinkle
Eric
E
Strachan
David P
DP
Mooser
Vincent
V
Stefansson
Kari
K
Reilly
Muredach P
MP
Samani
Nilesh J
NJ
Schunkert
Heribert
H
Cupples
L Adrienne
LA
Sandhu
Manjinder S
MS
Ridker
Paul M
PM
Rader
Daniel J
DJ
van Duijn
Cornelia M
CM
Peltonen
Leena
L
Abecasis
Gonçalo R
GR
Boehnke
Michael
M
Kathiresan
Sekar
S
D001741:Black or African American / Q000235:genetics; D000818:Animals; D044466:Asian People / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics / Q000628:therapy; D005060:Europe / Q000208:ethnology; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014280:Triglycerides / Q000097:blood; D044465:White People / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D017350:N-Acetylgalactosaminyltransferases; D054645:Protein Phosphatase 1; D014280:Triglycerides; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C498442:Ppp1r3b protein, mouse