New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Dupuis
Josée
J
Department of Biostatistics, Boston University School of Public Health, Massachusetts, USA.
Langenberg
Claudia
C
Prokopenko
Inga
I
Saxena
Richa
R
Soranzo
Nicole
N
Jackson
Anne U
AU
Wheeler
Eleanor
E
Glazer
Nicole L
NL
Bouatia-Naji
Nabila
N
Gloyn
Anna L
AL
Lindgren
Cecilia M
CM
Mägi
Reedik
R
Morris
Andrew P
AP
Randall
Joshua
J
Johnson
Toby
T
Elliott
Paul
P
Rybin
Denis
D
Thorleifsson
Gudmar
G
Steinthorsdottir
Valgerdur
V
Henneman
Peter
P
Grallert
Harald
H
Dehghan
Abbas
A
Hottenga
Jouke Jan
JJ
Franklin
Christopher S
CS
Navarro
Pau
P
Song
Kijoung
K
Goel
Anuj
A
Perry
John R B
JR
Egan
Josephine M
JM
Lajunen
Taina
T
Grarup
Niels
N
Sparsø
Thomas
T
Doney
Alex
A
Voight
Benjamin F
BF
Stringham
Heather M
HM
Li
Man
M
Kanoni
Stavroula
S
Shrader
Peter
P
Cavalcanti-Proença
Christine
C
Kumari
Meena
M
Qi
Lu
L
Timpson
Nicholas J
NJ
Gieger
Christian
C
Zabena
Carina
C
Rocheleau
Ghislain
G
Ingelsson
Erik
E
An
Ping
P
O'Connell
Jeffrey
J
Luan
Jian'an
J
Elliott
Amanda
A
McCarroll
Steven A
SA
Payne
Felicity
F
Roccasecca
Rosa Maria
RM
Pattou
François
F
Sethupathy
Praveen
P
Ardlie
Kristin
K
Ariyurek
Yavuz
Y
Balkau
Beverley
B
Barter
Philip
P
Beilby
John P
JP
Ben-Shlomo
Yoav
Y
Benediktsson
Rafn
R
Bennett
Amanda J
AJ
Bergmann
Sven
S
Bochud
Murielle
M
Boerwinkle
Eric
E
Bonnefond
Amélie
A
Bonnycastle
Lori L
LL
Borch-Johnsen
Knut
K
Böttcher
Yvonne
Y
Brunner
Eric
E
Bumpstead
Suzannah J
SJ
Charpentier
Guillaume
G
Chen
Yii-Der Ida
YD
Chines
Peter
P
Clarke
Robert
R
Coin
Lachlan J M
LJ
Cooper
Matthew N
MN
Cornelis
Marilyn
M
Crawford
Gabe
G
Crisponi
Laura
L
Day
Ian N M
IN
de Geus
Eco J C
EJ
Delplanque
Jerome
J
Dina
Christian
C
Erdos
Michael R
MR
Fedson
Annette C
AC
Fischer-Rosinsky
Antje
A
Forouhi
Nita G
NG
Fox
Caroline S
CS
Frants
Rune
R
Franzosi
Maria Grazia
MG
Galan
Pilar
P
Goodarzi
Mark O
MO
Graessler
Jürgen
J
Groves
Christopher J
CJ
Grundy
Scott
S
Gwilliam
Rhian
R
Gyllensten
Ulf
U
Hadjadj
Samy
S
Hallmans
Göran
G
Hammond
Naomi
N
Han
Xijing
X
Hartikainen
Anna-Liisa
AL
Hassanali
Neelam
N
Hayward
Caroline
C
Heath
Simon C
SC
Hercberg
Serge
S
Herder
Christian
C
Hicks
Andrew A
AA
Hillman
David R
DR
Hingorani
Aroon D
AD
Hofman
Albert
A
Hui
Jennie
J
Hung
Joe
J
Isomaa
Bo
B
Johnson
Paul R V
PR
Jørgensen
Torben
T
Jula
Antti
A
Kaakinen
Marika
M
Kaprio
Jaakko
J
Kesaniemi
Y Antero
YA
Kivimaki
Mika
M
Knight
Beatrice
B
Koskinen
Seppo
S
Kovacs
Peter
P
Kyvik
Kirsten Ohm
KO
Lathrop
G Mark
GM
Lawlor
Debbie A
DA
Le Bacquer
Olivier
O
Lecoeur
Cécile
C
Li
Yun
Y
Lyssenko
Valeriya
V
Mahley
Robert
R
Mangino
Massimo
M
Manning
Alisa K
AK
Martínez-Larrad
María Teresa
MT
McAteer
Jarred B
JB
McCulloch
Laura J
LJ
McPherson
Ruth
R
Meisinger
Christa
C
Melzer
David
D
Meyre
David
D
Mitchell
Braxton D
BD
Morken
Mario A
MA
Mukherjee
Sutapa
S
Naitza
Silvia
S
Narisu
Narisu
N
Neville
Matthew J
MJ
Oostra
Ben A
BA
Orrù
Marco
M
Pakyz
Ruth
R
Palmer
Colin N A
CN
Paolisso
Giuseppe
G
Pattaro
Cristian
C
Pearson
Daniel
D
Peden
John F
JF
Pedersen
Nancy L
NL
Perola
Markus
M
Pfeiffer
Andreas F H
AF
Pichler
Irene
I
Polasek
Ozren
O
Posthuma
Danielle
D
Potter
Simon C
SC
Pouta
Anneli
A
Province
Michael A
MA
Psaty
Bruce M
BM
Rathmann
Wolfgang
W
Rayner
Nigel W
NW
Rice
Kenneth
K
Ripatti
Samuli
S
Rivadeneira
Fernando
F
Roden
Michael
M
Rolandsson
Olov
O
Sandbaek
Annelli
A
Sandhu
Manjinder
M
Sanna
Serena
S
Sayer
Avan Aihie
AA
Scheet
Paul
P
Scott
Laura J
LJ
Seedorf
Udo
U
Sharp
Stephen J
SJ
Shields
Beverley
B
Sigurethsson
Gunnar
G
Sijbrands
Eric J G
EJ
Silveira
Angela
A
Simpson
Laila
L
Singleton
Andrew
A
Smith
Nicholas L
NL
Sovio
Ulla
U
Swift
Amy
A
Syddall
Holly
H
Syvänen
Ann-Christine
AC
Tanaka
Toshiko
T
Thorand
Barbara
B
Tichet
Jean
J
Tönjes
Anke
A
Tuomi
Tiinamaija
T
Uitterlinden
André G
AG
van Dijk
Ko Willems
KW
van Hoek
Mandy
M
Varma
Dhiraj
D
Visvikis-Siest
Sophie
S
Vitart
Veronique
V
Vogelzangs
Nicole
N
Waeber
Gérard
G
Wagner
Peter J
PJ
Walley
Andrew
A
Walters
G Bragi
GB
Ward
Kim L
KL
Watkins
Hugh
H
Weedon
Michael N
MN
Wild
Sarah H
SH
Willemsen
Gonneke
G
Witteman
Jaqueline C M
JC
Yarnell
John W G
JW
Zeggini
Eleftheria
E
Zelenika
Diana
D
Zethelius
Björn
B
Zhai
Guangju
G
Zhao
Jing Hua
JH
Zillikens
M Carola
MC
Borecki
Ingrid B
IB
Loos
Ruth J F
RJ
Meneton
Pierre
P
Magnusson
Patrik K E
PK
Nathan
David M
DM
Williams
Gordon H
GH
Hattersley
Andrew T
AT
Silander
Kaisa
K
Salomaa
Veikko
V
Smith
George Davey
GD
Bornstein
Stefan R
SR
Schwarz
Peter
P
Spranger
Joachim
J
Karpe
Fredrik
F
Shuldiner
Alan R
AR
Cooper
Cyrus
C
Dedoussis
George V
GV
Serrano-Ríos
Manuel
M
Morris
Andrew D
AD
Lind
Lars
L
Palmer
Lyle J
LJ
Hu
Frank B
FB
Franks
Paul W
PW
Ebrahim
Shah
S
Marmot
Michael
M
Kao
W H Linda
WH
Pankow
James S
JS
Sampson
Michael J
MJ
Kuusisto
Johanna
J
Laakso
Markku
M
Hansen
Torben
T
Pedersen
Oluf
O
Pramstaller
Peter Paul
PP
Wichmann
H Erich
HE
Illig
Thomas
T
Rudan
Igor
I
Wright
Alan F
AF
Stumvoll
Michael
M
Campbell
Harry
H
Wilson
James F
JF
Bergman
Richard N
RN
Buchanan
Thomas A
TA
Collins
Francis S
FS
Mohlke
Karen L
KL
Tuomilehto
Jaakko
J
Valle
Timo T
TT
Altshuler
David
D
Rotter
Jerome I
JI
Siscovick
David S
DS
Penninx
Brenda W J H
BW
Boomsma
Dorret I
DI
Deloukas
Panos
P
Spector
Timothy D
TD
Frayling
Timothy M
TM
Ferrucci
Luigi
L
Kong
Augustine
A
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
van Duijn
Cornelia M
CM
Aulchenko
Yurii S
YS
Cao
Antonio
A
Scuteri
Angelo
A
Schlessinger
David
D
Uda
Manuela
M
Ruokonen
Aimo
A
Jarvelin
Marjo-Riitta
MR
Waterworth
Dawn M
DM
Vollenweider
Peter
P
Peltonen
Leena
L
Mooser
Vincent
V
Abecasis
Goncalo R
GR
Wareham
Nicholas J
NJ
Sladek
Robert
R
Froguel
Philippe
P
Watanabe
Richard M
RM
Meigs
James B
JB
Groop
Leif
L
Boehnke
Michael
M
McCarthy
Mark I
MI
Florez
Jose C
JC
Barroso
Inês
I
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics; D030541:Databases, Genetic; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005215:Fasting / Q000097:blood*; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable; D015203:Reproducibility of Results
D001786:Blood Glucose; D000090943:Delta-5 Fatty Acid Desaturase; C000716847:FADS1 protein, human