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

@article{Morris2012LargescaleAA,
  title={Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes},
  author={Andrew P. Morris and Benjamin F. Voight and Tanya M. Teslovich and Teresa Ferreira and Ayellet V. Segr{\`e} and Valgerdur Steinthorsdottir and Rona J. Strawbridge and Hassan Khan and Harald Grallert and Anubha Mahajan and Inga Prokopenko and Hyun Min Kang and Christian Dina and T{\~o}nu Esko and Ross M Fraser and Stavroula Kanoni and Ashish Kumar and Vasiliki Lagou and Claudia Langenberg and Jian’an Luan and Cecilia M. Lindgren and Martina M{\"u}ller-Nurasyid and Sonali Pechlivanis and Nigel William Rayner and Laura J. Scott and Steven Wiltshire and Loic Yengo and Leena Kinnunen and Elizabeth J. Rossin and Soumya Raychaudhuri and Andrew D. Johnson and Antigone S. Dimas and Ruth J. F. Loos and Sailaja Vedantam and Han Chen and Jose C. Florez and Caroline S Fox and Ching‐Ti Liu and Denis Rybin and David J Couper and Wen Hong Linda Kao and Man Li and Marilyn C. Cornelis and Peter Kraft and Qi Sun and Rob M. van Dam and Heather M. Stringham and Peter S. Chines and Krista Fischer and Pierre Fontanillas and Oddgeir Lingaas Holmen and Sarah E. Hunt and Anne U. Jackson and Augustine Kong and Robert Lawrence and Julia Meyer and John R. B. Perry and Carl G. P. Platou and Simon C. Potter and Emil Rehnberg and Neil R. Robertson and Suthesh Sivapalaratnam and Alena Stan{\vc}{\'a}kov{\'a} and Kathleen E. Stirrups and Gudmar Thorleifsson and Emmi Tikkanen and Andrew R. Wood and Peter Almgren and Mustafa Atalay and Rafn Benediktsson and Lori L Bonnycastle and Noël P. Burtt and Jason P. Carey and Guillaume Charpentier and Andrew Crenshaw and Alex S. F. Doney and Mozhgan Dorkhan and Sarah Edkins and Valur Emilsson and Elodie Eury and Tom J. Fors{\'e}n and Karl Gertow and Bruna Gigante and George B. Grant and Christopher J. Groves and Candace Guiducci and Christian Herder and {\'A}str{\'a}dur B. Hreidarsson and Jennie Hui and Alan L James and Anna Jonsson and Wolfgang Rathmann and Norman Klopp and Jasmina Kravic and Kaarel Krjut{\vs}kov and Cordelia Langford and Karin Leander and Eero Lindholm and St{\'e}phane Lobbens and Satu M{\"a}nnist{\"o} and Ghazala K. Mirza and Thomas W. M{\"u}hleisen and Bill (A.W.) Musk and Melissa Parkin and Loukianos S. Rallidis and Jouko Saramies and Bengt Sennblad and Sonia Shah and Gunnar Sigurðsson and Angela Silveira and Gerald Steinbach and Barbara Thorand and Joseph Trakalo and Fabrizio Veglia and Roman Wennauer and Wendy Winckler and Delilah Zabaneh and Harry Campbell and Cornelia M. van Duijn and Andr{\'e} G. Uitterlinden and Albert Hofman and Eric J.G. Sijbrands and Gonçalo R. Abecasis and Katharine R. Owen and Eleftheria Zeggini and Mieke D. Trip and Nita G. Forouhi and Ann-Christine Syv{\"a}nen and Johan Gunnar Eriksson and Leena Peltonen and Markus M. N{\"o}then and Beverley Balkau and Colin N. A. Palmer and Valeriya Lyssenko and Tiinamaija Tuomi and Bo Isomaa and David J. Hunter and Lu Qi and Alan R. Shuldiner and Michael Roden and In{\^e}s Barroso and Tom Wilsgaard and John P. Beilby and Kees G. Hovingh and Jackie F. Price and James F. Wilson and Rainer Rauramaa and Timo A. Lakka and Lars Lind and George V. Dedoussis and Inger Nj{\o}lstad and Nancy L. Pedersen and Kay-Tee Khaw and Nicholas J. Wareham and Sirkka Keinanen-Kiukaanniemi and Timo E. Saaristo and eeva Korpi-hy{\"o}v{\"a}lti and Juha T Saltevo and Markku Laakso and Johanna Kuusisto and Andres Metspalu and Francis S. Collins and Karen L. Mohlke and Richard N. Bergman and Jaakko Tuomilehto and Bernhard Otto Boehm and Christian Gieger and Kristian Hveem and Stéphane Cauchi and Philippe Froguel and Damiano Baldassarre and Elena Tremoli and Steve E. Humphries and Danish Saleheen and John Danesh and Erik Ingelsson and Samuli Ripatti and Veikko V Salomaa and Raimund Erbel and Karl-Heinz J{\"o}ckel and Susanne Moebus and Annette Peters and Thomas Illig and Ulf de Faire and Anders Hamsten and Andrew D. Morris and Peter Donnelly and Timothy M. Frayling and Andrew T. Hattersley and Eric Boerwinkle and Olle Melander and Sekar Kathiresan and Peter M. Nilsson and Panos Deloukas and Unnur Thorsteinsd{\'o}ttir and Leif C. Groop and K{\'a}ri Stef{\'a}nsson and Frank B. Hu and James S. Pankow and Jos{\'e}e Dupuis and James B. Meigs and David M Altshuler and Michael Boehnke and Mark I. McCarthy},
  journal={Nature genetics},
  year={2012},
  volume={44},
  pages={981 - 990}
}
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… 

Insights into the Genetic Susceptibility to Type 2 Diabetes from Genome-Wide Association Studies of Obesity-Related Traits

The implications of these large-scale genome-wide association studies for obesity and T2D are discussed, the overlap of loci for obesity-related traits and T1D is investigated, and potential mechanisms that affect T2d susceptibility are highlighted.

Progress in defining the genetic contribution to type 2 diabetes susceptibility.

  • A. Morris
  • Biology, Medicine
    Current opinion in genetics & development
  • 2018

Insights into the Genetic Susceptibility to Type 2 Diabetes from Genome-Wide Association Studies of Glycaemic Traits

Important mechanistic insights have been gained regarding the physiological role of T2D loci in disease predisposition through the elucidation of their contribution to glycaemic trait variability, and further investigation is warranted to define causal variants within these loci.

Genome-Wide Association Studies of Type 2 Diabetes

Current efforts to identify the causative genetic mutations in these loci and the molecular mechanisms through which they exert their effects have the potential to make far-reaching contributions to the understanding of molecular basis of T2D and the development of novel strategies for patient care.

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

A significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association is observed, and considerable improvements in the fine-mapping resolution of common variant association signals at several T1D susceptibility loci are observed.

Recent Developments in the Genetic and Genomic Basis of Type 2 Diabetes

Progress made over the past year is described to expand genome wide association studies, to characterize the mechanisms through which diabetes risk loci operate, and to define the processes involved in diabetes predisposition.

Genetics of Type 2 Diabetes: Insights into the Pathogenesis and Its Clinical Application

This review covers the major genetic studies on the risk of type 2 diabetes based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.

Fine Mapping of Type 2 Diabetes Susceptibility Loci

  • A. Morris
  • Biology, Medicine
    Current Diabetes Reports
  • 2014
Available approaches for assaying genetic variation across loci and statistical methods to determine the most likely causal variants in the region are described and the utility of trans-ethnic meta-analysis for fine mapping is considered by leveraging the differences in the structure of linkage disequilibrium between diverse populations.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations and further functional analysis of these newly discovered loci will further improve the understanding of glycemic control.
...

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Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes

These findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect and underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 1 diabetes.

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

By combining genome-wide association data from 8,130 individuals with type 2 diabetes and 38,987 controls of European descent and following up previously unidentified meta-analysis signals, 12 new T2D association signals are identified with combined P < 5 × 10−8.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations and further functional analysis of these newly discovered loci will further improve the understanding of glycemic control.

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

A genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes, with convincing support for 19 additional T1D-associated loci5–13, all with allelic odds ratios (ORs) of less than 1.3.

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A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

Identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, may lead to a better understanding of differences in the molecular pathogenesis of type 2 diabetes among various populations.

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

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