Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Jennifer Wessel; Audrey Y Chu; Sara M Willems; Shuai Wang; Hanieh Yaghootkar; Jennifer A Brody; Marco Dauriz; Marie-France Hivert; Sridharan Raghavan; Leonard Lipovich; Bertha Hidalgo; Keolu Fox; Jennifer E Huffman; Ping An; Yingchang Lu; Laura J Rasmussen-Torvik; Niels Grarup; Margaret G Ehm; Li Li; Abigail S Baldridge; Alena Stančáková; Ravinder Abrol; Céline Besse; Anne Boland; Jette Bork-Jensen; Myriam Fornage; Daniel F Freitag; Melissa E Garcia; Xiuqing Guo; Kazuo Hara; Aaron Isaacs; Johanna Jakobsdottir; Leslie A Lange; Jill C Layton; Man Li; Jing Hua Zhao; Karina Meidtner; Alanna C Morrison; Mike A Nalls; Marjolein J Peters; Maria Sabater-Lleal; Claudia Schurmann; Angela Silveira; Albert V Smith; Lorraine Southam; Marcus H Stoiber; Rona J Strawbridge; Kent D Taylor; Tibor V Varga; Kristine H Allin; Najaf Amin; Jennifer L Aponte; Tin Aung; Caterina Barbieri; Nathan A Bihlmeyer; Michael Boehnke; Cristina Bombieri; Donald W Bowden; Sean M Burns; Yuning Chen; Yii-Der I Chen; Ching-Yu Cheng; Adolfo Correa; Jacek Czajkowski; Abbas Dehghan; Georg B Ehret; Gudny Eiriksdottir; Stefan A Escher; Aliki-Eleni Farmaki; Mattias Frånberg; Giovanni Gambaro; Franco Giulianini; William A Goddard; Anuj Goel; Omri Gottesman; Megan L Grove; Stefan Gustafsson; Yang Hai; Göran Hallmans; Jiyoung Heo; Per Hoffmann; Mohammad K Ikram; Richard A Jensen; Marit E Jørgensen; Torben Jørgensen; Maria Karaleftheri; Chiea C Khor; Andrea Kirkpatrick; Aldi T Kraja; Johanna Kuusisto; Ethan M Lange; I T Lee; Wen-Jane Lee; Aaron Leong; Jiemin Liao; Chunyu Liu; Yongmei Liu; Cecilia M Lindgren; Allan Linneberg; Giovanni Malerba; Vasiliki Mamakou; Eirini Marouli; Nisa M Maruthur; Angela Matchan; Roberta Mckean-Cowdin; Olga Mcleod; Ginger A Metcalf; Karen L Mohlke; Donna M Muzny; Ioanna Ntalla; Nicholette D Palmer; Dorota Pasko; Andreas Peter; Nigel W Rayner; Frida Renström; Ken Rice; Cinzia F Sala; Bengt Sennblad; Ioannis Serafetinidis; Jennifer A Smith; Nicole Soranzo; Elizabeth K Speliotes; Eli A Stahl; Kathleen Stirrups; Nikos Tentolouris; Anastasia Thanopoulou; Mina Torres; Michela Traglia; Emmanouil Tsafantakis; Sundas Javad; Lisa R Yanek; Eleni Zengini; Diane M Becker; Joshua C Bis; James B Brown; L Adrienne Cupples; Torben Hansen; Erik Ingelsson; Andrew J Karter; Carlos Lorenzo; Rasika A Mathias; Jill M Norris; Gina M Peloso; Null- H Sheu; Daniela Toniolo; Dhananjay Vaidya; Rohit Varma; Lynne E Wagenknecht; Heiner Boeing; Erwin P Bottinger; George Dedoussis; Panos Deloukas; Ele Ferrannini; Oscar H Franco; Paul W Franks; Richard A Gibbs; Vilmundur Gudnason; Anders Hamsten; Tamara B Harris; Andrew T Hattersley; Caroline Hayward; Albert Hofman; Jan-Håkan Jansson; Claudia Langenberg; Lenore J Launer; Daniel Levy; Ben A Oostra; Christopher J O’donnell; Stephen O’rahilly; Sandosh Padmanabhan; James S Pankow; Ozren Polasek; Michael A Province; Stephen S Rich; Paul M Ridker; Igor Rudan; Matthias B Schulze; Blair H Smith; André G Uitterlinden; Mark Walker; Hugh Watkins; Tien Y Wong; Eleftheria Zeggini; Stephen J Sharp; Nita G Forouhi; Nicola D Kerrison; Debora Me Lucarelli; Matt Sims; Inês Barroso; Mark I Mccarthy; Larraitz Arriola; Beverley Balkau; Aurelio Barricarte; Carlos Gonzalez; Sara Grioni; Rudolf Kaaks; Timothy J Key; Carmen Navarro; Peter M Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; J Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; Nadia Slimani; Anne Tjonneland; Rosario Tumino; Daphne L van der A; Yvonne T van der Schouw; Elio Riboli; Markku Laakso; Ingrid B Borecki; Daniel I Chasman; Oluf Pedersen; Bruce M Psaty; E Shyong Tai; Cornelia M van Duijn; Nicholas J Wareham; Dawn M Waterworth; Eric Boerwinkle; W H Linda Kao; Jose C Florez; Ruth J F Loos; James G Wilson; Timothy M Frayling; David S Siscovick; Josée Dupuis; Jerome I Rotter; James B Meigs; Robert A Scott; Mark O Goodarzi

doi:10.1038/ncomms6897

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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Jennifer Wessel, Audrey Y Chu, Sara M Willems, Shuai Wang, Hanieh Yaghootkar, Jennifer A Brody, Marco Dauriz, Marie-France Hivert, Sridharan Raghavan, Leonard Lipovich, …

Nature Communications, Vol.6(5897)

29/01/2015

DOI: https://doi.org/10.1038/ncomms6897

Abstract

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

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Title: Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Creators - without role: Jennifer Wessel - Richard M. Fairbanks Foundation
Audrey Y Chu - Brigham and Women's Hospital
Sara M Willems - Erasmus MC
Shuai Wang - Boston University
Hanieh Yaghootkar - University of Exeter
Jennifer A Brody - University of Washington
Marco Dauriz - Massachusetts General Hospital
Marie-France Hivert - Massachusetts General Hospital
Sridharan Raghavan - Massachusetts General Hospital
Leonard Lipovich - Wayne State University
Bertha Hidalgo - University of Alabama at Birmingham
Keolu Fox - University of Washington
Jennifer E Huffman - Framingham Heart Study
Ping An - Washington University in St. Louis
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Laura J Rasmussen-Torvik - Northwestern University
Niels Grarup - University of Copenhagen
Margaret G Ehm - GlaxoSmithKline
Li Li - Université de Montpellier, Montpellier Recherche en Management - MRM
Abigail S Baldridge - Northwestern University
Alena Stančáková - University of Eastern Finland
Ravinder Abrol - Cedars-Sinai Medical Center
Céline Besse - Genoscope
Anne Boland - Commissariat à l'Énergie Atomique et aux Énergies Alternatives
Jette Bork-Jensen - Novo Nordisk Foundation
Myriam Fornage - Brown Foundation
Daniel F Freitag - Wellcome Sanger Institute
Melissa E Garcia - National Institute on Aging
Xiuqing Guo - Harbor–UCLA Medical Center
Kazuo Hara - Icahn School of Medicine at Mount Sinai
Aaron Isaacs - Erasmus MC
Johanna Jakobsdottir - Icelandic Heart Association
Leslie A Lange - University of North Carolina at Chapel Hill
Jill C Layton - Indiana University – Purdue University Indianapolis
Man Li - Brigham and Women's Hospital
Jing Hua Zhao
Karina Meidtner - German Institute of Human Nutrition
Alanna C Morrison - The University of Texas Health Science Center at Houston
Mike A Nalls - National Institute on Aging
Marjolein J Peters - Erasmus MC
Maria Sabater-Lleal - Karolinska Institutet
Claudia Schurmann - Icahn School of Medicine at Mount Sinai
Angela Silveira - Karolinska Institutet
Albert V Smith - Icelandic Heart Association
Lorraine Southam - Wellcome Sanger Institute
Marcus H Stoiber - Lawrence Berkeley National Laboratory
Rona J Strawbridge - Karolinska Institutet
Kent D Taylor - The Lundquist Institute
Tibor V Varga - Skåne University Hospital
Kristine H Allin - Novo Nordisk Foundation
Najaf Amin - Erasmus MC
Jennifer L Aponte - GlaxoSmithKline
Tin Aung - Singapore National Eye Center
Caterina Barbieri - San Raffaele University of Rome
Nathan A Bihlmeyer - Johns Hopkins Medicine
Michael Boehnke - University of Michigan–Ann Arbor
Cristina Bombieri - University of Verona
Donald W Bowden - Wake Forest University
Sean M Burns - Massachusetts General Hospital
Yuning Chen - Boston University
Yii-Der I Chen
Ching-Yu Cheng
Adolfo Correa - University of Mississippi Medical Center
Jacek Czajkowski - Washington University in St. Louis
Abbas Dehghan - Erasmus MC
Georg B Ehret - Johns Hopkins University
Gudny Eiriksdottir
Stefan A Escher - Lund University
Aliki-Eleni Farmaki - Harokopio University of Athens
Mattias Frånberg - Karolinska Institutet
Giovanni Gambaro - Agostino Gemelli University Polyclinic
Franco Giulianini - Brigham and Women's Hospital
William A Goddard - California Institute of Technology
Anuj Goel - Centre for Human Genetics
Omri Gottesman - Icahn School of Medicine at Mount Sinai
Megan L Grove - The University of Texas Health Science Center at Houston
Stefan Gustafsson - Uppsala University
Yang Hai - Harbor–UCLA Medical Center
Göran Hallmans - Umeå University
Jiyoung Heo - Sangmyung University
Per Hoffmann - Life & Brain
Mohammad K Ikram - Singapore National Eye Center
Richard A Jensen - University of Washington
Marit E Jørgensen - Steno Diabetes Centers
Torben Jørgensen - Glostrup Hospital
Maria Karaleftheri - Athens Medical Center
Chiea C Khor - National University of Singapore
Andrea Kirkpatrick - California Institute of Technology
Aldi T Kraja - Washington University in St. Louis
Johanna Kuusisto - Kuopio University Hospital
Ethan M Lange - University of North Carolina at Chapel Hill
I T Lee - Taichung Veterans General Hospital
Wen-Jane Lee
Aaron Leong - Harvard University
Jiemin Liao - Singapore National Eye Center
Chunyu Liu - National Heart Lung and Blood Institute
Yongmei Liu - Wake Forest University
Cecilia M Lindgren - Centre for Human Genetics
Allan Linneberg - Glostrup Hospital
Giovanni Malerba - University of Verona
Vasiliki Mamakou - National and Kapodistrian University of Athens
Eirini Marouli - Harokopio University of Athens
Nisa M Maruthur - Johns Hopkins Medicine
Angela Matchan - Wellcome Sanger Institute
Roberta Mckean-Cowdin - University of Southern California
Olga Mcleod - Karolinska Institutet
Ginger A Metcalf - Baylor College of Medicine
Karen L Mohlke - University of North Carolina at Chapel Hill
Donna M Muzny - Baylor College of Medicine
Ioanna Ntalla
Nicholette D Palmer - Wake Forest University
Dorota Pasko - University of Exeter
Andreas Peter - University of Tübingen
Nigel W Rayner - Wellcome Sanger Institute
Frida Renström - Skåne University Hospital
Ken Rice
Cinzia F Sala - San Raffaele University of Rome
Bengt Sennblad - Karolinska Institutet
Ioannis Serafetinidis
Jennifer A Smith - University of Michigan–Ann Arbor
Nicole Soranzo - Wellcome Sanger Institute
Elizabeth K Speliotes - University of Michigan–Ann Arbor
Eli A Stahl - Icahn School of Medicine at Mount Sinai
Kathleen Stirrups - Wellcome Sanger Institute
Nikos Tentolouris - Laiko General Hospital of Athens
Anastasia Thanopoulou - Hippocration General Hospital
Mina Torres - University of Southern California
Michela Traglia - San Raffaele University of Rome
Emmanouil Tsafantakis
Sundas Javad - University of Cambridge
Lisa R Yanek - Johns Hopkins Medicine
Eleni Zengini
Diane M Becker - Johns Hopkins Medicine
Joshua C Bis - University of Washington
James B Brown - Lawrence Berkeley National Laboratory
L Adrienne Cupples
Torben Hansen - Novo Nordisk Foundation
Erik Ingelsson - Uppsala University
Andrew J Karter - Kaiser Permanente
Carlos Lorenzo - The University of Texas Health Science Center at San Antonio
Rasika A Mathias - Johns Hopkins Medicine
Jill M Norris - University of Colorado Denver
Gina M Peloso - Broad Institute
Null- H Sheu
Daniela Toniolo - San Raffaele University of Rome
Dhananjay Vaidya - Johns Hopkins Medicine
Rohit Varma - University of Southern California
Lynne E Wagenknecht - Wake Forest University
Heiner Boeing - German Institute of Human Nutrition
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
George Dedoussis - Harokopio University of Athens
Panos Deloukas - Queen Mary University of London
Ele Ferrannini - Istituto di Fisiologia Clinica
Oscar H Franco - Erasmus MC
Paul W Franks - Lund University
Richard A Gibbs - Baylor College of Medicine
Vilmundur Gudnason
Anders Hamsten - Karolinska Institutet
Tamara B Harris - National Institute on Aging
Andrew T Hattersley - University of Exeter
Caroline Hayward - MRC Institute of Genetics and Molecular Medicine
Albert Hofman - Erasmus MC
Jan-Håkan Jansson - Umeå University
Claudia Langenberg - MRC Epidemiology Unit
Lenore J Launer - National Institute on Aging
Daniel Levy - National Heart Lung and Blood Institute
Ben A Oostra - Erasmus MC
Christopher J O’donnell - Harvard University
Stephen O’rahilly - Wellcome/MRC Institute of Metabolic Science
Sandosh Padmanabhan - University of Glasgow
James S Pankow - University of Minnesota
Ozren Polasek - University of Split
Michael A Province - Washington University in St. Louis
Stephen S Rich - University of Virginia
Paul M Ridker - Brigham and Women's Hospital
Igor Rudan - University of Edinburgh
Matthias B Schulze - German Institute of Human Nutrition
Blair H Smith - University of Dundee
André G Uitterlinden - Erasmus MC
Mark Walker - Newcastle University
Hugh Watkins - Centre for Human Genetics
Tien Y Wong - Duke-NUS Medical School
Eleftheria Zeggini - Wellcome Sanger Institute
Stephen J Sharp - MRC Epidemiology Unit
Nita G Forouhi - MRC Epidemiology Unit
Nicola D Kerrison - MRC Epidemiology Unit
Debora Me Lucarelli - MRC Epidemiology Unit
Matt Sims - MRC Epidemiology Unit
Inês Barroso - Wellcome Sanger Institute
Mark I Mccarthy - Centre for Human Genetics
Larraitz Arriola
Beverley Balkau - Centre de recherche en Epidémiologie et Santé des Populations
Aurelio Barricarte - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Carlos Gonzalez - Institut Català d'Oncologia
Sara Grioni - National Centre for Disease Prevention and Control
Rudolf Kaaks - German Cancer Research Center
Timothy J Key - University of Oxford
Carmen Navarro - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Peter M Nilsson - Skåne University Hospital
Kim Overvad - Aarhus University
Domenico Palli - Piedmont Reference Center for Epidemiology and Cancer Prevention
Salvatore Panico - Federico II University Hospital
J Ramón Quirós - Gobierno del Principado de Asturias
Olov Rolandsson - Umeå University
Carlotta Sacerdote - Piedmont Reference Center for Epidemiology and Cancer Prevention
Nadia Slimani - Centre International de Recherche sur le Cancer
Anne Tjonneland
Rosario Tumino
Daphne L van der A - National Institute for Public Health and the Environment
Yvonne T van der Schouw - University Medical Center Utrecht
Elio Riboli - Imperial College London
Markku Laakso - University of Eastern Finland
Ingrid B Borecki - Washington University in St. Louis
Daniel I Chasman - Brigham and Women's Hospital
Oluf Pedersen - Novo Nordisk Foundation
Bruce M Psaty - University of Washington
E Shyong Tai
Cornelia M van Duijn - Centre for Medical Systems Biology
Nicholas J Wareham - MRC Epidemiology Unit
Dawn M Waterworth - GlaxoSmithKline
Eric Boerwinkle - Baylor College of Medicine
W H Linda Kao
Jose C Florez - Broad Institute
Ruth J F Loos - Child Health and Development Institute
James G Wilson - University of Mississippi Medical Center
Timothy M Frayling - University of Exeter
David S Siscovick - New York Academy of Medicine
Josée Dupuis - Boston University
Jerome I Rotter - The Lundquist Institute
James B Meigs - Harvard University
Robert A Scott - MRC Epidemiology Unit
Mark O Goodarzi - Cedars-Sinai Medical Center
Publication Details: Nature Communications, Vol.6(5897)
Identifiers: 9935770709311
Academic Unit: Montpellier Recherche en Management - MRM
Language: English
Resource Type: Journal article
Local Fields: cea-04601787