Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
Voight
Benjamin F
BF
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
Scott
Laura J
LJ
Steinthorsdottir
Valgerdur
V
Morris
Andrew P
AP
Dina
Christian
C
Welch
Ryan P
RP
Zeggini
Eleftheria
E
Huth
Cornelia
C
Aulchenko
Yurii S
YS
Thorleifsson
Gudmar
G
McCulloch
Laura J
LJ
Ferreira
Teresa
T
Grallert
Harald
H
Amin
Najaf
N
Wu
Guanming
G
Willer
Cristen J
CJ
Raychaudhuri
Soumya
S
McCarroll
Steve A
SA
Langenberg
Claudia
C
Hofmann
Oliver M
OM
Dupuis
Josée
J
Qi
Lu
L
Segrè
Ayellet V
AV
van Hoek
Mandy
M
Navarro
Pau
P
Ardlie
Kristin
K
Balkau
Beverley
B
Benediktsson
Rafn
R
Bennett
Amanda J
AJ
Blagieva
Roza
R
Boerwinkle
Eric
E
Bonnycastle
Lori L
LL
Bengtsson Boström
Kristina
K
Bravenboer
Bert
B
Bumpstead
Suzannah
S
Burtt
Noisël P
NP
Charpentier
Guillaume
G
Chines
Peter S
PS
Cornelis
Marilyn
M
Couper
David J
DJ
Crawford
Gabe
G
Doney
Alex S F
AS
Elliott
Katherine S
KS
Elliott
Amanda L
AL
Erdos
Michael R
MR
Fox
Caroline S
CS
Franklin
Christopher S
CS
Ganser
Martha
M
Gieger
Christian
C
Grarup
Niels
N
Green
Todd
T
Griffin
Simon
S
Groves
Christopher J
CJ
Guiducci
Candace
C
Hadjadj
Samy
S
Hassanali
Neelam
N
Herder
Christian
C
Isomaa
Bo
B
Jackson
Anne U
AU
Johnson
Paul R V
PR
Jørgensen
Torben
T
Kao
Wen H L
WH
Klopp
Norman
N
Kong
Augustine
A
Kraft
Peter
P
Kuusisto
Johanna
J
Lauritzen
Torsten
T
Li
Man
M
Lieverse
Aloysius
A
Lindgren
Cecilia M
CM
Lyssenko
Valeriya
V
Marre
Michel
M
Meitinger
Thomas
T
Midthjell
Kristian
K
Morken
Mario A
MA
Narisu
Narisu
N
Nilsson
Peter
P
Owen
Katharine R
KR
Payne
Felicity
F
Perry
John R B
JR
Petersen
Ann-Kristin
AK
Platou
Carl
C
Proença
Christine
C
Prokopenko
Inga
I
Rathmann
Wolfgang
W
Rayner
N William
NW
Robertson
Neil R
NR
Rocheleau
Ghislain
G
Roden
Michael
M
Sampson
Michael J
MJ
Saxena
Richa
R
Shields
Beverley M
BM
Shrader
Peter
P
Sigurdsson
Gunnar
G
Sparsø
Thomas
T
Strassburger
Klaus
K
Stringham
Heather M
HM
Sun
Qi
Q
Swift
Amy J
AJ
Thorand
Barbara
B
Tichet
Jean
J
Tuomi
Tiinamaija
T
van Dam
Rob M
RM
van Haeften
Timon W
TW
van Herpt
Thijs
T
van Vliet-Ostaptchouk
Jana V
JV
Walters
G Bragi
GB
Weedon
Michael N
MN
Wijmenga
Cisca
C
Witteman
Jacqueline
J
Bergman
Richard N
RN
Cauchi
Stephane
S
Collins
Francis S
FS
Gloyn
Anna L
AL
Gyllensten
Ulf
U
Hansen
Torben
T
Hide
Winston A
WA
Hitman
Graham A
GA
Hofman
Albert
A
Hunter
David J
DJ
Hveem
Kristian
K
Laakso
Markku
M
Mohlke
Karen L
KL
Morris
Andrew D
AD
Palmer
Colin N A
CN
Pramstaller
Peter P
PP
Rudan
Igor
I
Sijbrands
Eric
E
Stein
Lincoln D
LD
Tuomilehto
Jaakko
J
Uitterlinden
Andre
A
Walker
Mark
M
Wareham
Nicholas J
NJ
Watanabe
Richard M
RM
Abecasis
Gonçalo R
GR
Boehm
Bernhard O
BO
Campbell
Harry
H
Daly
Mark J
MJ
Hattersley
Andrew T
AT
Hu
Frank B
FB
Meigs
James B
JB
Pankow
James S
JS
Pedersen
Oluf
O
Wichmann
H-Erich
HE
Barroso
Inês
I
Florez
Jose C
JC
Frayling
Timothy M
TM
Groop
Leif
L
Sladek
Rob
R
Thorsteinsdottir
Unnur
U
Wilson
James F
JF
Illig
Thomas
T
Froguel
Philippe
P
van Duijn
Cornelia M
CM
Stefansson
Kari
K
Altshuler
David
D
Boehnke
Michael
M
McCarthy
Mark I
MI
D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D005215:Fasting / Q000097:blood; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D015201:Meta-Analysis as Topic; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
D001786:Blood Glucose; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051657:KCNQ1 Potassium Channel; D054639:Mitogen-Activated Protein Kinase Phosphatases; C104821:DUSP9 protein, human; D054637:Dual-Specificity Phosphatases