DOI: 10.1038/ng.2383

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

Andrew P. Morris,Benjamin F. Voight,Tanya M. Teslovich,Teresa Ferreira,Ayellet V. Segrè,Valgerður Steinthórsdóttir,Rona J. Strawbridge,Hassan Khan,Harald Grallert,Anubha Mahajan,Inga Prokopenko,Hyun Min Kang,Christian Dina,Tõnu Esko,Ross M. Fraser,Stavroula Kanoni,Ashish Kumar,Vasiliki Lagou,Claudia Langenberg,Jian’an Luan,Cecilia M. Lindgren,Martina Müller‐Nurasyid,Sonali Pechlivanis,Nigel W. Rayner,Laura J. Scott,Steven Wiltshire,Loïc Yengo,Leena Kinnunen,Elizabeth J. Rossin,Soumya Raychaudhuri,Andrew D. Johnson,Antigone S. Dimas,Ruth J.F. Loos,Sailaja Vedantam,Han Chen,José C. Florez,Caroline S. Fox,Ching‐Ti Liu,Denis Rybin,David J. Couper,W. H. Linda Kao,Man Li,Marilyn C. Cornelis,Peter Kraft,Qi Sun,Rob M. van Dam,Heather M. Stringham,Peter S. Chines,Krista Fischer,Pierre Fontanillas,Oddgeir L. Holmen,Sarah Hunt,Anne Jackson,Augustine Kong,Robert Lawrence,Julia Meyer,John Perry,Carl Platou,Simon Potter,Emil Rehnberg,Neil Robertson,Suthesh Sivapalaratnam,Alena Stančáková,Kathleen Stirrups,Guðmar Þorleifsson,Emmi Tikkanen,Andrew R. Wood,Peter Almgren,Mustafa Atalay,Rafn Benediktsson,Lori L. Bonnycastle,Noël P. Burtt,Jason Carey,G. Charpentier,Andrew Crenshaw,Alex S.F. Doney,Mozhgan Dorkhan,Sarah Edkins,Valur Emilsson,Elodie Eury,Tom Forsén,Karl Gertow,Bruna Gigante,George Grant,Christopher J. Groves,Candace Guiducci,Christian Herder,Ástráður B. Hreiðarsson,Jennie Hui,Alan James,Anna Jonsson,Wolfgang Rathmann,Norman Klopp,Jasmina Kravić,Kaarel Krjutškov,Cordelia Langford,Karin Leander,Eero Lindholm,Stéphane Lobbens,Satu Männistö,Ghazala Mirza,Thomas W. Mühleisen,Bill Musk,Melissa Parkin,Lοukianos S. Rallidis,Jouko Saramies,Bengt Sennblad,Sonia Shah,Gunnar Sigurðsson,Angela Silveira,Gerald Steinbach,Barbara Thorand,Joseph Trakalo,Fabrizio Veglia,Roman Wennauer,Wendy Winckler,Delilah Zabaneh,Harry Campbell,Cornelia M. van Duijn,André G. Uitterlinden,Albert Hofman,Eric J.G. Sijbrands,Gonçalo R. Abecasis,Katharine R. Owen,Eleftheria Zeggini,Mieke D. Trip,Nita G. Forouhi,Ann‐Christine Syvänen,Johan G. Eriksson,Leena Peltonen,Markus M. Nöthen,Beverley Balkau,Colin N.A. Palmer,Valeriya Lyssenko,Tiinamaija Tuomi,Bo Isomaa,David J. Hunter,Lü Qi,Alan R. Shuldiner,Michael Roden,Inês Barroso,Tom Wilsgaard,John Beilby,Kees Hovingh,Jackie F. Price,James F. Wilson,Rainer Rauramaa,Timo A. Lakka,Lars Lind,George Dedoussis,Inger Njølstad,Nancy L. Pedersen,Kay‐Tee Khaw,Nicholas J. Wareham,Sirkka Keinänen‐Kiukaanniemi,Timo Saaristo,Eeva Korpi-Hyövälti,Juha Saltevo,Markku Laakso,Johanna Kuusisto,Andres Metspalu,Francis S. Collins,Karen L. Mohlke,Richard N. Bergman,Jaakko Tuomilehto,Bernhard O. Boehm,Christian Gieger,Kristian Hveem,Stéphane Cauchi,Philippe Froguel,Damiano Baldassarre,Elena Tremoli,Steve E. Humphries,Danish Saleheen,John Danesh,Erik Ingelsson,Samuli Ripatti,Veikko Salomaa,Raimund Erbel,Karl‐Heinz Jöckel,Susanne Moebus,Annette Peters,Thomas Illig,Ulf dé Fairé,Anders Hamsten,Andrew D. Morris,Peter Donnelly,Timothy M. Frayling,Andrew T. Hattersley,Eric Boerwinkle,Olle Melander,Sekar Kathiresan,Peter M. Nilsson,Panos Deloukas,Unnur Þorsteinsdóttir,Leif Groop,Kári Stefánsson,James S. Pankow,Josée Dupuis,James B. Meigs,David Altshuler,Michael Boehnke,Mark I. McCarthy

Biology

Genetic architecture

Genome-wide association study

2012

Mark McCarthy, Michael Boehnke, Andrew Morris and colleagues perform large-scale association analyses using the Metabochip to gain insights into the genetic architecture of type 2 diabetes. They report several new susceptibility loci, including two that show sex-differentiated effects on disease risk. 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.

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“Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes” is a paper by Andrew P. Morris Benjamin F. Voight Tanya M. Teslovich Teresa Ferreira Ayellet V. Segrè Valgerður Steinthórsdóttir Rona J. Strawbridge Hassan Khan Harald Grallert Anubha Mahajan Inga Prokopenko Hyun Min Kang Christian Dina Tõnu Esko Ross M. Fraser Stavroula Kanoni Ashish Kumar Vasiliki Lagou Claudia Langenberg Jian’an Luan Cecilia M. Lindgren Martina Müller‐Nurasyid Sonali Pechlivanis Nigel W. Rayner Laura J. Scott Steven Wiltshire Loïc Yengo Leena Kinnunen Elizabeth J. Rossin Soumya Raychaudhuri Andrew D. Johnson Antigone S. Dimas Ruth J.F. Loos Sailaja Vedantam Han Chen José C. Florez Caroline S. Fox Ching‐Ti Liu Denis Rybin David J. Couper W. H. Linda Kao Man Li Marilyn C. Cornelis Peter Kraft Qi Sun Rob M. van Dam Heather M. Stringham Peter S. Chines Krista Fischer Pierre Fontanillas Oddgeir L. Holmen Sarah Hunt Anne Jackson Augustine Kong Robert Lawrence Julia Meyer John Perry Carl Platou Simon Potter Emil Rehnberg Neil Robertson Suthesh Sivapalaratnam Alena Stančáková Kathleen Stirrups Guðmar Þorleifsson Emmi Tikkanen Andrew R. Wood Peter Almgren Mustafa Atalay Rafn Benediktsson Lori L. Bonnycastle Noël P. Burtt Jason Carey G. Charpentier Andrew Crenshaw Alex S.F. Doney Mozhgan Dorkhan Sarah Edkins Valur Emilsson Elodie Eury Tom Forsén Karl Gertow Bruna Gigante George Grant Christopher J. Groves Candace Guiducci Christian Herder Ástráður B. Hreiðarsson Jennie Hui Alan James Anna Jonsson Wolfgang Rathmann Norman Klopp Jasmina Kravić Kaarel Krjutškov Cordelia Langford Karin Leander Eero Lindholm Stéphane Lobbens Satu Männistö Ghazala Mirza Thomas W. Mühleisen Bill Musk Melissa Parkin Lοukianos S. Rallidis Jouko Saramies Bengt Sennblad Sonia Shah Gunnar Sigurðsson Angela Silveira Gerald Steinbach Barbara Thorand Joseph Trakalo Fabrizio Veglia Roman Wennauer Wendy Winckler Delilah Zabaneh Harry Campbell Cornelia M. van Duijn André G. Uitterlinden Albert Hofman Eric J.G. Sijbrands Gonçalo R. Abecasis Katharine R. Owen Eleftheria Zeggini Mieke D. Trip Nita G. Forouhi Ann‐Christine Syvänen Johan G. Eriksson Leena Peltonen Markus M. Nöthen Beverley Balkau Colin N.A. Palmer Valeriya Lyssenko Tiinamaija Tuomi Bo Isomaa David J. Hunter Lü Qi Alan R. Shuldiner Michael Roden Inês Barroso Tom Wilsgaard John Beilby Kees Hovingh Jackie F. Price James F. Wilson Rainer Rauramaa Timo A. Lakka Lars Lind George Dedoussis Inger Njølstad Nancy L. Pedersen Kay‐Tee Khaw Nicholas J. Wareham Sirkka Keinänen‐Kiukaanniemi Timo Saaristo Eeva Korpi-Hyövälti Juha Saltevo Markku Laakso Johanna Kuusisto Andres Metspalu Francis S. Collins Karen L. Mohlke Richard N. Bergman Jaakko Tuomilehto Bernhard O. Boehm Christian Gieger Kristian Hveem Stéphane Cauchi Philippe Froguel Damiano Baldassarre Elena Tremoli Steve E. Humphries Danish Saleheen John Danesh Erik Ingelsson Samuli Ripatti Veikko Salomaa Raimund Erbel Karl‐Heinz Jöckel Susanne Moebus Annette Peters Thomas Illig Ulf dé Fairé Anders Hamsten Andrew D. Morris Peter Donnelly Timothy M. Frayling Andrew T. Hattersley Eric Boerwinkle Olle Melander Sekar Kathiresan Peter M. Nilsson Panos Deloukas Unnur Þorsteinsdóttir Leif Groop Kári Stefánsson James S. Pankow Josée Dupuis James B. Meigs David Altshuler Michael Boehnke Mark I. McCarthy published in 2012. It has an Open Access status of “green”. You can read and download a PDF Full Text of this paper here.