Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
Zeggini
Eleftheria
E
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Scott
Laura J
LJ
Saxena
Richa
R
Voight
Benjamin F
BF
Marchini
Jonathan L
JL
Hu
Tianle
T
de Bakker
Paul I W
PI
Abecasis
Gonçalo R
GR
Almgren
Peter
P
Andersen
Gitte
G
Ardlie
Kristin
K
Boström
Kristina Bengtsson
KB
Bergman
Richard N
RN
Bonnycastle
Lori L
LL
Borch-Johnsen
Knut
K
Burtt
Noël P
NP
Chen
Hong
H
Chines
Peter S
PS
Daly
Mark J
MJ
Deodhar
Parimal
P
Ding
Chia-Jen
CJ
Doney
Alex S F
AS
Duren
William L
WL
Elliott
Katherine S
KS
Erdos
Michael R
MR
Frayling
Timothy M
TM
Freathy
Rachel M
RM
Gianniny
Lauren
L
Grallert
Harald
H
Grarup
Niels
N
Groves
Christopher J
CJ
Guiducci
Candace
C
Hansen
Torben
T
Herder
Christian
C
Hitman
Graham A
GA
Hughes
Thomas E
TE
Isomaa
Bo
B
Jackson
Anne U
AU
Jørgensen
Torben
T
Kong
Augustine
A
Kubalanza
Kari
K
Kuruvilla
Finny G
FG
Kuusisto
Johanna
J
Langenberg
Claudia
C
Lango
Hana
H
Lauritzen
Torsten
T
Li
Yun
Y
Lindgren
Cecilia M
CM
Lyssenko
Valeriya
V
Marvelle
Amanda F
AF
Meisinger
Christa
C
Midthjell
Kristian
K
Mohlke
Karen L
KL
Morken
Mario A
MA
Morris
Andrew D
AD
Narisu
Narisu
N
Nilsson
Peter
P
Owen
Katharine R
KR
Palmer
Colin N A
CN
Payne
Felicity
F
Perry
John R B
JR
Pettersen
Elin
E
Platou
Carl
C
Prokopenko
Inga
I
Qi
Lu
L
Qin
Li
L
Rayner
Nigel W
NW
Rees
Matthew
M
Roix
Jeffrey J
JJ
Sandbaek
Anelli
A
Shields
Beverley
B
Sjögren
Marketa
M
Steinthorsdottir
Valgerdur
V
Stringham
Heather M
HM
Swift
Amy J
AJ
Thorleifsson
Gudmar
G
Thorsteinsdottir
Unnur
U
Timpson
Nicholas J
NJ
Tuomi
Tiinamaija
T
Tuomilehto
Jaakko
J
Walker
Mark
M
Watanabe
Richard M
RM
Weedon
Michael N
MN
Willer
Cristen J
CJ
Illig
Thomas
T
Hveem
Kristian
K
Hu
Frank B
FB
Laakso
Markku
M
Stefansson
Kari
K
Pedersen
Oluf
O
Wareham
Nicholas J
NJ
Barroso
Inês
I
Hattersley
Andrew T
AT
Collins
Francis S
FS
Groop
Leif
L
McCarthy
Mark I
MI
Boehnke
Michael
M
Altshuler
David
D
D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D020641:Polymorphism, Single Nucleotide