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Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.

TitleLarge-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Publication TypeJournal Article
Year of Publication2012
AuthorsMorris AP, Voight BF, Teslovich TM, et al.
Secondary AuthorsMcCarthy MI
Corporate AuthorsWellcome Trust Case Control Consortium, Meta-Analyses of Glucose and Insulin-related traits Consortium(MAGIC) Investigators, Genetic Investigation of Anthropometric Traits(GIANT) Consortium, Asian Genetic Epidemiology Network–Type 2 Diabetes(AGEN-T2D) Consortium, South Asian Type 2 Diabetes(SAT2D) Consortium, DIAbetes Genetics Replication and Meta-analysis(DIAGRAM) Consortium
JournalNat Genet
Volume44
Issue9
Pagination981-90
Date Published2012 Sep
ISSN1546-1718
KeywordsCase-Control Studies, Diabetes Mellitus, Type 2, Female, Genes, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Pakistan, Polymorphism, Single Nucleotide, Sex Factors
Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

DOI10.1038/ng.2383
Alternate JournalNat Genet
PubMed ID22885922
PubMed Central IDPMC3442244
Grant ListHHSN268201100006C / HL / NHLBI NIH HHS / United States
DK062370 / DK / NIDDK NIH HHS / United States
R01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
AG04563 / AG / NIA NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
CZB/4/710 / CSO_ / Chief Scientist Office / United Kingdom
R01 DK073490 / DK / NIDDK NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
CZB/4/672 / CSO_ / Chief Scientist Office / United Kingdom
098017 / WT_ / Wellcome Trust / United Kingdom
R01 DK058845 / DK / NIDDK NIH HHS / United States
GR098051 / WT_ / Wellcome Trust / United Kingdom
RG/08/008/25291 / BHF_ / British Heart Foundation / United Kingdom
R56 DK062370 / DK / NIDDK NIH HHS / United States
N01HG65403 / HG / NHGRI NIH HHS / United States
DK058845 / DK / NIDDK NIH HHS / United States
MC_UP_A100_1003 / MRC_ / Medical Research Council / United Kingdom
1R21NS064908 / NS / NINDS NIH HHS / United States
GR077016 / WT_ / Wellcome Trust / United Kingdom
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
AG10175 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 DK085545 / DK / NIDDK NIH HHS / United States
G19/35 / MRC_ / Medical Research Council / United Kingdom
GR086596 / WT_ / Wellcome Trust / United Kingdom
HHSN268201100005G / HL / NHLBI NIH HHS / United States
RG2008/08 / BHF_ / British Heart Foundation / United Kingdom
HHSN268201100008I / HL / NHLBI NIH HHS / United States
G0100222 / MRC_ / Medical Research Council / United Kingdom
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HG006513 / HG / NHGRI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom
AG028555 / AG / NIA NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
G8802774 / MRC_ / Medical Research Council / United Kingdom
G1000143 / MRC_ / Medical Research Council / United Kingdom
G0902037 / MRC_ / Medical Research Council / United Kingdom
U01HG004399 / HG / NHGRI NIH HHS / United States
1Z01HG000024 / HG / NHGRI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
DHCS/07/07/008 / DH_ / Department of Health / United Kingdom
GR076113 / WT_ / Wellcome Trust / United Kingdom
R01 DK062370 / DK / NIDDK NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
GR084711 / WT_ / Wellcome Trust / United Kingdom
DK072193 / DK / NIDDK NIH HHS / United States
MC_U106179471 / MRC_ / Medical Research Council / United Kingdom
R01 AG028555 / AG / NIA NIH HHS / United States
090367 / WT_ / Wellcome Trust / United Kingdom
R01HL087641 / HL / NHLBI NIH HHS / United States
GR083270 / WT_ / Wellcome Trust / United Kingdom
GR081682 / WT_ / Wellcome Trust / United Kingdom
HHSN268201100005I / HL / NHLBI NIH HHS / United States
G0401527 / MRC_ / Medical Research Council / United Kingdom
G0701863 / MRC_ / Medical Research Council / United Kingdom
Z01 HG000024 / ImNIH / Intramural NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
090532 / WT_ / Wellcome Trust / United Kingdom
G0000649 / MRC_ / Medical Research Council / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
AG08861 / AG / NIA NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
AG08724 / AG / NIA NIH HHS / United States
DK078616 / DK / NIDDK NIH HHS / United States
064890 / WT_ / Wellcome Trust / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
UL1 RR029887 / RR / NCRR NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
CA055075 / CA / NCI NIH HHS / United States
GR072960 / WT_ / Wellcome Trust / United Kingdom
GR090532 / WT_ / Wellcome Trust / United Kingdom
DK073490 / DK / NIDDK NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R21 NS064908 / NS / NINDS NIH HHS / United States
DK080140 / DK / NIDDK NIH HHS / United States
R01 AG010175 / AG / NIA NIH HHS / United States
RG/98002 / BHF_ / British Heart Foundation / United Kingdom
U01 HG004399 / HG / NHGRI NIH HHS / United States
081682 / WT_ / Wellcome Trust / United Kingdom
G0601261 / MRC_ / Medical Research Council / United Kingdom
/ CRUK_ / Cancer Research UK / United Kingdom
GR083948 / WT_ / Wellcome Trust / United Kingdom
R01HL086694 / HL / NHLBI NIH HHS / United States
RG/07/008/23674 / BHF_ / British Heart Foundation / United Kingdom