Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Geoffrey A. Walford; Stefan Gustafsson; Denis Rybin; Alena Stancakova; Han Chen; Ching-Ti Liu; Jaeyoung Hong; Richard A. Jensen; Ken Rice; Andrew P. Morris; Reedik Magi; Anke Toenjes; Inga Prokopenko; Marcus E. Kleber; Graciela Delgado; Guenther Silbernagel; Anne U. Jackson; Emil V. Appel; Niels Grarup; Joshua P. Lewis; May E. Montasser; Claes Landenvall; Harald Staiger; Jian'an Luan; Timothy M. Frayling; Michael N. Weedon; Weijia Xie; Sonsoles Morcillo; Maria Teresa Martinez-Larrad; Mary L. Biggs; Yii-Der Ida Chen; Arturo Corbaton-Anchuelo; Kristine Faerch; Juan Miguel Gomez-Zumaquero; Mark O. Goodarzi; Jorge R. Kizer; Heikki A. Koistinen; Aaron Leong; Lars Lind; Cecilia Lindgren; Fausto Machicao; Alisa K. Manning; Gracia Maria Martin-Nunez; Gemma Rojo-Martinez; Jerome I. Rotter; David S. Siscovick; Joseph M. Zmuda; Zhongyang Zhang; Manuel Serrano-Rios; Ulf Smith; Federico Soriguer; Torben Hansen; Torben J. Jorgensen; Allan Linnenberg; Oluf Pedersen; Mark Walker; Claudia Langenberg; Robert A. Scott; Nicholas J. Wareham; Andreas Fritsche; Hans-Ulrich Haering; Norbert Stefan; Leif Groop; Jeff R. O'Connell; Michael Boehnke; Richard N. Bergman; Francis S. Collins; Karen L. Mohlke; Jaakko Tuomilehto; Winfried Maerz; Peter Kovacs; Michael Stumvoll; Bruce M. Psaty; Johanna Kuusisto; Markku Laakso; James B. Meigs; Josee Dupuis; Erik Ingelsson; Jose C. Florez

doi:10.2337/db16-0199

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Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

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Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Geoffrey A. Walford, Stefan Gustafsson, Denis Rybin, Alena Stancakova, Han Chen, Ching-Ti Liu, Jaeyoung Hong, Richard A. Jensen, Ken Rice, Andrew P. Morris, …

Diabetes (New York, N.Y.), Vol.65(10), pp.3200-3211

01/10/2016

DOI: https://doi.org/10.2337/db16-0199

PMID: 27416945

Abstract

Endocrinology & Metabolism

Life Sciences & Biomedicine

Science & Technology

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 x 10(-11)), rs12454712 (BCL2; P = 2.7 x 10(-8)), and rs10506418 (FAM19A2; P = 1.9 x 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

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Title: Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
Creators: Geoffrey A. Walford - Massachusetts General Hospital
Stefan Gustafsson - Uppsala University
Denis Rybin - Boston University
Alena Stancakova - University of Eastern Finland
Han Chen - Boston University
Ching-Ti Liu - Boston University
Jaeyoung Hong - Boston University
Richard A. Jensen - University of Washington
Ken Rice - University of Washington
Andrew P. Morris - University of Liverpool
Reedik Magi - University of Tartu
Anke Toenjes - College Station Medical Center
Inga Prokopenko - Wellcome Centre for Human Genetics
Marcus E. Kleber - University Hospital Heidelberg
Graciela Delgado - University Medical Centre Mannheim
Guenther Silbernagel - University of Graz
Anne U. Jackson - University of Michigan–Ann Arbor
Emil V. Appel - Novo Nordisk Foundation
Niels Grarup - Novo Nordisk Foundation
Joshua P. Lewis - University of Maryland, Baltimore
May E. Montasser - University of Maryland, Baltimore
Claes Landenvall - Uppsala University
Harald Staiger - German Center for Diabetes Research
Jian'an Luan - University of Cambridge
Timothy M. Frayling - University of Exeter
Michael N. Weedon - University of Exeter
Weijia Xie - University of Exeter
Sonsoles Morcillo - Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition
Maria Teresa Martinez-Larrad - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Mary L. Biggs - University of Washington
Yii-Der Ida Chen - UCLA Medical Center
Arturo Corbaton-Anchuelo - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Kristine Faerch - Steno Diabet Ctr, Gentofte, Denmark
Juan Miguel Gomez-Zumaquero - Inst Invest Biomed Malaga IBIMA, Malaga, Spain
Mark O. Goodarzi - Cedars-Sinai Medical Center
Jorge R. Kizer - Albert Einstein College of Medicine
Heikki A. Koistinen - Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland
Aaron Leong - Massachusetts General Hospital
Lars Lind - Uppsala University
Cecilia Lindgren - University of Oxford
Fausto Machicao - German Center for Diabetes Research
Alisa K. Manning - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Gracia Maria Martin-Nunez - Hosp Reg Univ & Virgen de la Victoria Malaga, Dept Endocrinol & Nutr, Malaga, Spain
Gemma Rojo-Martinez - Hosp Reg Univ Malaga, Dept Endocrinol & Nutr, Malaga, Spain
Jerome I. Rotter - Harbor–UCLA Medical Center
David S. Siscovick - University of Washington
Joseph M. Zmuda - University of Pittsburgh
Zhongyang Zhang - Icahn School of Medicine at Mount Sinai
Manuel Serrano-Rios - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Ulf Smith - University of Gothenburg
Federico Soriguer - Hospital Regional Universitario de Málaga
Torben Hansen - Novo Nordisk Foundation
Torben J. Jorgensen - University of Copenhagen
Allan Linnenberg - Capital Region of Denmark
Oluf Pedersen - University of Copenhagen
Mark Walker - Newcastle University
Claudia Langenberg - MRC Epidemiology Unit
Robert A. Scott - University of Cambridge
Nicholas J. Wareham - University of Cambridge
Andreas Fritsche - University Children's Hospital Tübingen
Hans-Ulrich Haering - University of Tübingen
Norbert Stefan - Heinrich Heine University Düsseldorf
Leif Groop - University of Helsinki
Jeff R. O'Connell - Supreme Council Of Health
Michael Boehnke - University of Michigan–Ann Arbor
Richard N. Bergman - Cedars-Sinai Medical Center
Francis S. Collins - National Human Genome Research Institute
Karen L. Mohlke - University of North Carolina at Chapel Hill
Jaakko Tuomilehto - King Abdulaziz University
Winfried Maerz - Heidelberg University
Peter Kovacs - IFB Adiposity Diseases
Michael Stumvoll - Leipzig University
Bruce M. Psaty - University of Washington
Johanna Kuusisto - Kuopio University Hospital
Markku Laakso - University of Eastern Finland
James B. Meigs - Harvard University
Josee Dupuis - Boston University
Erik Ingelsson - Science for Life Laboratory
Jose C. Florez - Massachusetts General Hospital
Publication Details: Diabetes (New York, N.Y.), Vol.65(10), pp.3200-3211
Publisher: Amer Diabetes Assoc
Number of pages: 12
Date published: 01/10/2016
Grant note: the Danish Diabetes Association Danish Pharmaceutical Association German Diabetes Association A28 / INTERREG-IV-Oberrhein-Program Perklen Foundation Wissenschaftsoffensive PI11/00880; PS09/02117 / Instituto de Salud Carlos III; Spanish Government SFB 1052; SPP 1629 TO 718/2-1 / German Research Council (DFG); German Research Foundation (DFG) 20120197 / Swedish Heart-Lung Foundation Boehringer Ingelheim Foundation; Boehringer Ingelheim
Identifiers: 99928743702346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

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