Common variants at 30 loci contribute to polygenic dyslipidemia.
Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
Kathiresan
Sekar
S
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Willer
Cristen J
CJ
Peloso
Gina M
GM
Demissie
Serkalem
S
Musunuru
Kiran
K
Schadt
Eric E
EE
Kaplan
Lee
L
Bennett
Derrick
D
Li
Yun
Y
Tanaka
Toshiko
T
Voight
Benjamin F
BF
Bonnycastle
Lori L
LL
Jackson
Anne U
AU
Crawford
Gabriel
G
Surti
Aarti
A
Guiducci
Candace
C
Burtt
Noel P
NP
Parish
Sarah
S
Clarke
Robert
R
Zelenika
Diana
D
Kubalanza
Kari A
KA
Morken
Mario A
MA
Scott
Laura J
LJ
Stringham
Heather M
HM
Galan
Pilar
P
Swift
Amy J
AJ
Kuusisto
Johanna
J
Bergman
Richard N
RN
Sundvall
Jouko
J
Laakso
Markku
M
Ferrucci
Luigi
L
Scheet
Paul
P
Sanna
Serena
S
Uda
Manuela
M
Yang
Qiong
Q
Lunetta
Kathryn L
KL
Dupuis
Josée
J
de Bakker
Paul I W
PI
O'Donnell
Christopher J
CJ
Chambers
John C
JC
Kooner
Jaspal S
JS
Hercberg
Serge
S
Meneton
Pierre
P
Lakatta
Edward G
EG
Scuteri
Angelo
A
Schlessinger
David
D
Tuomilehto
Jaakko
J
Collins
Francis S
FS
Groop
Leif
L
Altshuler
David
D
Collins
Rory
R
Lathrop
G Mark
GM
Melander
Olle
O
Salomaa
Veikko
V
Peltonen
Leena
L
Orho-Melander
Marju
M
Ordovas
Jose M
JM
Boehnke
Michael
M
Abecasis
Gonçalo R
GR
Mohlke
Karen L
KL
Cupples
L Adrienne
LA
D000328:Adult; D000483:Alleles; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D000090943:Delta-5 Fatty Acid Desaturase; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013577:Syndrome; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D000090943:Delta-5 Fatty Acid Desaturase; D012333:RNA, Messenger; D014280:Triglycerides; C000716847:FADS1 protein, human