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

Authors:
Dr Eirini Marouli
Dr Eirini Marouli
School of Health Science and Education
Peter Andreas
Peter Andreas
Trent University
Researcher
Plant Physiology and Genetics
Peterborough, Ontario | Canada
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-DerI 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 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 Wayne H-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 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

Nat Commun 2015 Jan 29;6:5897. Epub 2015 Jan 29.

1] Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

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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http://dx.doi.org/10.1038/ncomms6897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311266PMC
January 2015
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