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GWAS Study

A central role for GRB10 in regulation of islet function in man.

Prokopenko I, Poon W, Mägi R et al.

24699409 PubMed ID
GWAS Study Type
25282 Participants
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Chapter I

Publication Details

Comprehensive information about this research publication

Authors

PI
Prokopenko I
PW
Poon W
MR
Mägi R
PB
Prasad B R
SS
Salehi SA
AP
Almgren P
OP
Osmark P
BN
Bouatia-Naji N
WN
Wierup N
FT
Fall T
SA
Stančáková A
BA
Barker A
LV
Lagou V
OC
Osmond C
XW
Xie W
LJ
Lahti J
JA
Jackson AU
CY
Cheng YC
LJ
Liu J
OJ
O'Connell JR
BP
Blomstedt PA
FJ
Fadista J
AS
Alkayyali S
DT
Dayeh T
AE
Ahlqvist E
TJ
Taneera J
LC
Lecoeur C
KA
Kumar A
HO
Hansson O
HK
Hansson K
VB
Voight BF
KH
Kang HM
LC
Levy-Marchal C
VV
Vatin V
PA
Palotie A
SA
Syvänen AC
MA
Mari A
WM
Weedon MN
LR
Loos RJ
OK
Ong KK
NP
Nilsson P
IB
Isomaa B
TT
Tuomi T
WN
Wareham NJ
SM
Stumvoll M
WE
Widen E
LT
Lakka TA
LC
Langenberg C
TA
Tönjes A
RR
Rauramaa R
KJ
Kuusisto J
FT
Frayling TM
FP
Froguel P
WM
Walker M
EJ
Eriksson JG
LC
Ling C
KP
Kovacs P
IE
Ingelsson E
MM
McCarthy MI
SA
Shuldiner AR
SK
Silver KD
LM
Laakso M
GL
Groop L
LV
Lyssenko V
Chapter II

Abstract

Summary of the research findings

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

up to 4,565 European individuals, up to 413 Old Order Amish (founder/genetic isolate) individuals

Chapter III

Study Statistics

Key metrics and study information

25282
Total Participants
GWAS
Study Type
Yes
Replicated
20,514 non-diabetic individuals
Replication Participants
European
Ancestry
U.S., Austria, France, Germany, Netherlands, Switzerland, Denmark, Finland, Republic of Ireland, Sweden, U.K., Greece, Italy, Montenegro, Serbia, Spain
Recruitment Country
Chapter IV

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