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PMID: 22885922 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 44 ·No. 9 ·2012-09-00 ·Pages 981-90

Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H, Mahajan A, Prokopenko I, Kang HM, Dina C, Esko T, Fraser RM, Kanoni S, Kumar A, Lagou V, Langenberg C, Luan J, Lindgren CM, Müller-Nurasyid M, Pechlivanis S, Rayner NW, Scott LJ, Wiltshire S, Yengo L, Kinnunen L, Rossin EJ, Raychaudhuri S, Johnson AD, Dimas AS, Loos RJ, Vedantam S, Chen H, Florez JC, Fox C, Liu CT, Rybin D, Couper DJ, Kao WH, Li M, Cornelis MC, Kraft P, Sun Q, van Dam RM, Stringham HM, Chines PS, Fischer K, Fontanillas P, Holmen OL, Hunt SE, Jackson AU, Kong A, Lawrence R, Meyer J, Perry JR, Platou CG, Potter S, Rehnberg E, Robertson N, Sivapalaratnam S, Stančáková A, Stirrups K, Thorleifsson G, Tikkanen E, Wood AR, Almgren P, Atalay M, Benediktsson R, Bonnycastle LL, Burtt N, Carey J, Charpentier G, Crenshaw AT, Doney AS, Dorkhan M, Edkins S, Emilsson V, Eury E, Forsen T, Gertow K, Gigante B, Grant GB, Groves CJ, Guiducci C, Herder C, Hreidarsson AB, Hui J, James A, Jonsson A, Rathmann W, Klopp N, Kravic J, Krjutškov K, Langford C, Leander K, Lindholm E, Lobbens S, Männistö S, Mirza G, Mühleisen TW, Musk B, Parkin M, Rallidis L, Saramies J, Sennblad B, Shah S, Sigurðsson G, Silveira A, Steinbach G, Thorand B, Trakalo J, Veglia F, Wennauer R, Winckler W, Zabaneh D, Campbell H, van Duijn C, Uitterlinden AG, Hofman A, Sijbrands E, Abecasis GR, Owen KR, Zeggini E, Trip MD, Forouhi NG, Syvänen AC, Eriksson JG, Peltonen L, Nöthen MM, Balkau B, Palmer CN, Lyssenko V, Tuomi T, Isomaa B, Hunter DJ, Qi L, Wellcome 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, Shuldiner AR, Roden M, Barroso I, Wilsgaard T, Beilby J, Hovingh K, Price JF, Wilson JF, Rauramaa R, Lakka TA, Lind L, Dedoussis G, Njølstad I, Pedersen NL, Khaw KT, Wareham NJ, Keinanen-Kiukaanniemi SM, Saaristo TE, Korpi-Hyövälti E, Saltevo J, Laakso M, Kuusisto J, Metspalu A, Collins FS, Mohlke KL, Bergman RN, Tuomilehto J, Boehm BO, Gieger C, Hveem K, Cauchi S, Froguel P, Baldassarre D, Tremoli E, Humphries SE, Saleheen D, Danesh J, Ingelsson E, Ripatti S, Salomaa V, Erbel R, Jöckel KH, Moebus S, Peters A, Illig T, de Faire U, Hamsten A, Morris AD, Donnelly PJ, Frayling TM, Hattersley AT, Boerwinkle E, Melander O, Kathiresan S, Nilsson PM, Deloukas P, Thorsteinsdottir U, Groop LC, Stefansson K, Hu F, Pankow JS, Dupuis J, Meigs JB, Altshuler D, Boehnke M, McCarthy MI, DIAbetes Genetics Replication And Meta-analysis DIAGRAM Consortium

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.

MeSH Terms
Case-Control Studies Diabetes Mellitus, Type 2/epidemiology,genetics Female Genes/physiology Genetic Predisposition to Disease/genetics Genome-Wide Association Study/statistics & numerical data Humans Linkage Disequilibrium Male Pakistan/epidemiology Polymorphism, Single Nucleotide/physiology Sex Factors
Authors & Affiliations
210 authors, click to expand affiliations / ORCID
Morris Andrew P
Wellcome Trust Centre for Human Genetics, University of Oxford, UK. [email protected]
Voight Benjamin F
Teslovich Tanya M
Ferreira Teresa
Segrè Ayellet V
Steinthorsdottir Valgerdur
Strawbridge Rona J
Khan Hassan
Grallert Harald
Mahajan Anubha
Prokopenko Inga
Kang Hyun Min
Dina Christian
Esko Tonu
Fraser Ross M
Kanoni Stavroula
Kumar Ashish
Lagou Vasiliki
Langenberg Claudia
Luan Jian'an
Lindgren Cecilia M
Müller-Nurasyid Martina
Pechlivanis Sonali
Rayner N William
Scott Laura J
Wiltshire Steven
Yengo Loic
Kinnunen Leena
Rossin Elizabeth J
Raychaudhuri Soumya
Johnson Andrew D
Dimas Antigone S
Loos Ruth J F
Vedantam Sailaja
Chen Han
Florez Jose C
Fox Caroline
Liu Ching-Ti
Rybin Denis
Couper David J
Kao Wen Hong L
Li Man
Cornelis Marilyn C
Kraft Peter
Sun Qi
van Dam Rob M
Stringham Heather M
Chines Peter S
Fischer Krista
Fontanillas Pierre
Holmen Oddgeir L
Hunt Sarah E
Jackson Anne U
Kong Augustine
Lawrence Robert
Meyer Julia
Perry John R B
Platou Carl G P
Potter Simon
Rehnberg Emil
Robertson Neil
Sivapalaratnam Suthesh
Stančáková Alena
Stirrups Kathleen
Thorleifsson Gudmar
Tikkanen Emmi
Wood Andrew R
Almgren Peter
Atalay Mustafa
Benediktsson Rafn
Bonnycastle Lori L
Burtt Noël
Carey Jason
Charpentier Guillaume
Crenshaw Andrew T
Doney Alex S F
Dorkhan Mozhgan
Edkins Sarah
Emilsson Valur
Eury Elodie
Forsen Tom
Gertow Karl
Gigante Bruna
Grant George B
Groves Christopher J
Guiducci Candace
Herder Christian
Hreidarsson Astradur B
Hui Jennie
James Alan
Jonsson Anna
Rathmann Wolfgang
Klopp Norman
Kravic Jasmina
Krjutškov Kaarel
Langford Cordelia
Leander Karin
Lindholm Eero
Lobbens Stéphane
Männistö Satu
Mirza Ghazala
Mühleisen Thomas W
Musk Bill
Parkin Melissa
Rallidis Loukianos
Saramies Jouko
Sennblad Bengt
Shah Sonia
Sigurðsson Gunnar
Silveira Angela
Steinbach Gerald
Thorand Barbara
Trakalo Joseph
Veglia Fabrizio
Wennauer Roman
Winckler Wendy
Zabaneh Delilah
Campbell Harry
van Duijn Cornelia
Uitterlinden Andre G
Hofman Albert
Sijbrands Eric
Abecasis Goncalo R
Owen Katharine R
Zeggini Eleftheria
Trip Mieke D
Forouhi Nita G
Syvänen Ann-Christine
Eriksson Johan G
Peltonen Leena
Nöthen Markus M
Balkau Beverley
Palmer Colin N A
Lyssenko Valeriya
Tuomi Tiinamaija
Isomaa Bo
Hunter David J
Qi Lu
Wellcome 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
Shuldiner Alan R
Roden Michael
Barroso Ines
Wilsgaard Tom
Beilby John
Hovingh Kees
Price Jackie F
Wilson James F
Rauramaa Rainer
Lakka Timo A
Lind Lars
Dedoussis George
Njølstad Inger
Pedersen Nancy L
Khaw Kay-Tee
Wareham Nicholas J
Keinanen-Kiukaanniemi Sirkka M
Saaristo Timo E
Korpi-Hyövälti Eeva
Saltevo Juha
Laakso Markku
Kuusisto Johanna
Metspalu Andres
Collins Francis S
Mohlke Karen L
Bergman Richard N
Tuomilehto Jaakko
Boehm Bernhard O
Gieger Christian
Hveem Kristian
Cauchi Stephane
Froguel Philippe
Baldassarre Damiano
Tremoli Elena
Humphries Steve E
Saleheen Danish
Danesh John
Ingelsson Erik
Ripatti Samuli
Salomaa Veikko
Erbel Raimund
Jöckel Karl-Heinz
Moebus Susanne
Peters Annette
Illig Thomas
de Faire Ulf
Hamsten Anders
Morris Andrew D
Donnelly Peter J
Frayling Timothy M
Hattersley Andrew T
Boerwinkle Eric
Melander Olle
Kathiresan Sekar
Nilsson Peter M
Deloukas Panos
Thorsteinsdottir Unnur
Groop Leif C
Stefansson Kari
Hu Frank
Pankow James S
Dupuis Josée
Meigs James B
Altshuler David
Boehnke Michael
McCarthy Mark I
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2383
Email
[email protected]
Published
2012-09-00
Epub
2012-00-12
Pages
981-90
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3442244
Subset
IM
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PubMed source DOI: 10.1038/ng.2383 PMC Full Text View journal details
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