A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Alisa Manning; Heather M. Highland; Jessica Gasser; Xueling Sim; Taru Tukiainen; Pierre Fontanillas; Niels Grarup; Manuel A. Rivas; Anubha Mahajan; Adam E. Locke; Pablo Cingolani; Tune H. Pers; Ana Vinuela; Andrew A. Brown; Ying Wu; Jason Flannick; Christian Fuchsberger; Eric R. Gamazon; Kyle J. Gaulton; Hae Kyung Im; Tanya M. Teslovich; Thomas W. Blackwell; Jette Bork-Jensen; Noel P. Burtt; Yuhui Chen; Todd Green; Christopher Hartl; Hyun Min Kang; Ashish Kumar; Claes Ladenvall; Clement Ma; Loukas Moutsianas; Richard D. Pearson; John R. B. Perry; N. William Rayner; Neil R. Robertson; Laura J. Scott; Martijn van de Bunt; Johan G. Eriksson; Antti Jula; Seppo Koskinen; Terho Lehtimaki; Aarno Palotie; Olli T. Raitakari; Suzanne B. R. Jacobs; Jennifer Wessel; Audrey Y. Chu; Robert A. Scott; Mark O. Goodarzi; Christine Blancher; Gemma Buck; David Buck; Peter S. Chines; Stacey Gabriel; Anette P. Gjesing; Christopher J. Groves; Mette Hollensted; Jeroen R. Huyghe; Anne U. Jackson; Goo Jun; Johanne Marie Justesen; Massimo Mangino; Jacquelyn Murphy; Matt Neville; Robert Onofrio; Kerrin S. Small; Heather M. Stringham; Joseph Trakalo; Eric Banks; Jason Carey; Mauricio O. Carneiro; Mark DePristo; Yossi Farjoun; Timothy Fennell; Jacqueline I. Goldstein; George Grant; Martin Hrabe de Angelis; Jared Maguire; Benjamin M. Neale; Ryan Poplin; Shaun Purcell; Thomas Schwarzmayr; Khalid Shakir; Joshua D. Smith; Tim M. Strom; Thomas Wieland; Jaana Lindstrom; Ivan Brandslund; Cramer Christensen; Gabriela L. Surdulescu; Timo A. Lakka; Alex S. F. Doney; Peter Nilsson; Nicholas J. Wareham; Claudia Langenberg; Tibor V. Varga; Paul W. Franks; Olov Rolandsson; Anders H. Rosengren; Vidya S. Farook; et al; Inga Prokopenko

doi:10.2337/db16-1329

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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Alisa Manning, Heather M. Highland, Jessica Gasser, Xueling Sim, Taru Tukiainen, Pierre Fontanillas, Niels Grarup, Manuel A. Rivas, Anubha Mahajan, Adam E. Locke, …

Diabetes (New York, N.Y.), Vol.66(7), pp.2019-2032

01/07/2017

DOI: https://doi.org/10.2337/db16-1329

PMID: 28341696

Abstract

Endocrinology & Metabolism

Life Sciences & Biomedicine

Science & Technology

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

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Title: A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
Creators: Alisa Manning - Broad Institute
Heather M. Highland - The University of Texas Health Science Center at Houston
Jessica Gasser - Broad Institute
Xueling Sim - University of Michigan–Ann Arbor
Taru Tukiainen - Broad Institute
Pierre Fontanillas - Broad Institute
Niels Grarup - University of Copenhagen
Manuel A. Rivas - Wellcome Centre for Human Genetics
Anubha Mahajan - Wellcome Centre for Human Genetics
Adam E. Locke - University of Michigan–Ann Arbor
Pablo Cingolani - McGill University
Tune H. Pers - University of Copenhagen
Ana Vinuela - King's College London
Andrew A. Brown - Wellcome Sanger Institute
Ying Wu - Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA
Jason Flannick - Broad Institute
Christian Fuchsberger - University of Michigan–Ann Arbor
Eric R. Gamazon - University of Chicago
Kyle J. Gaulton - University of California, San Diego
Hae Kyung Im - University of Chicago
Tanya M. Teslovich - University of Michigan–Ann Arbor
Thomas W. Blackwell - University of Michigan–Ann Arbor
Jette Bork-Jensen - University of Copenhagen
Noel P. Burtt - Broad Institute
Yuhui Chen - Wellcome Centre for Human Genetics
Todd Green - Broad Institute
Christopher Hartl - Broad Institute
Hyun Min Kang - University of Michigan–Ann Arbor
Ashish Kumar - University of Oxford
Claes Ladenvall - Lund University
Clement Ma - University of Michigan–Ann Arbor
Loukas Moutsianas - Wellcome Centre for Human Genetics
Richard D. Pearson - Wellcome Centre for Human Genetics
John R. B. Perry - University of Cambridge
N. William Rayner - Wellcome Centre for Human Genetics
Neil R. Robertson - University of Oxford
Laura J. Scott - University of Michigan–Ann Arbor
Martijn van de Bunt - Wellcome Centre for Human Genetics
Johan G. Eriksson - University of Helsinki
Antti Jula - Finnish Institute for Health and Welfare
Seppo Koskinen - Finnish Institute for Health and Welfare
Terho Lehtimaki - Fimlab
Aarno Palotie - Broad Institute
Olli T. Raitakari - University of Turku
Suzanne B. R. Jacobs - Broad Institute
Jennifer Wessel - Richard M. Fairbanks Foundation
Audrey Y. Chu - Brigham and Women's Hospital
Robert A. Scott - University of Cambridge
Mark O. Goodarzi - Cedars-Sinai Medical Center
Christine Blancher - Genomics
Gemma Buck - Genomics
David Buck - University of Oxford
Peter S. Chines - National Human Genome Research Institute
Stacey Gabriel - Broad Institute
Anette P. Gjesing - University of Copenhagen
Christopher J. Groves - Oxford Centre for Diabetes, Endocrinology and Metabolism
Mette Hollensted - University of Copenhagen
Jeroen R. Huyghe - University of Michigan–Ann Arbor
Anne U. Jackson - University of Michigan–Ann Arbor
Goo Jun - University of Michigan–Ann Arbor
Johanne Marie Justesen - Novo Nordisk Foundation
Massimo Mangino - King's College London
Jacquelyn Murphy - Broad Institute
Matt Neville - Oxford Centre for Diabetes, Endocrinology and Metabolism
Robert Onofrio - Broad Institute
Kerrin S. Small - King's College London
Heather M. Stringham - University of Michigan–Ann Arbor
Joseph Trakalo - Wellcome Centre for Human Genetics
Eric Banks - Broad Institute
Jason Carey - Broad Institute
Mauricio O. Carneiro - Broad Institute
Mark DePristo - Broad Institute
Yossi Farjoun - Broad Institute
Timothy Fennell - Broad Institute
Jacqueline I. Goldstein - Broad Institute
George Grant - Broad Institute
Martin Hrabe de Angelis - Helmholtz Zentrum München
Jared Maguire - Broad Institute
Benjamin M. Neale - Massachusetts General Hospital
Ryan Poplin - Broad Institute
Shaun Purcell - Broad Institute
Thomas Schwarzmayr - Helmholtz Zentrum München
Khalid Shakir - Broad Institute
Joshua D. Smith - University of Washington
Tim M. Strom - Helmholtz Zentrum München
Thomas Wieland - Helmholtz Zentrum München
Jaana Lindstrom - Finnish Institute for Health and Welfare
Ivan Brandslund - University of Southern Denmark
Cramer Christensen - Vejle Sygehus
Gabriela L. Surdulescu - King's College London
Timo A. Lakka - University of Eastern Finland
Alex S. F. Doney - Ninewells Hospital
Peter Nilsson - Lund University
Nicholas J. Wareham - MRC Epidemiology Unit
Claudia Langenberg - MRC Epidemiology Unit
Tibor V. Varga - Lund University
Paul W. Franks - Harvard University
Olov Rolandsson - Umeå University
Anders H. Rosengren - Lund University
Vidya S. Farook - Texas Biomedical Research Institute
et al
Inga Prokopenko - School of Biosciences
Publication Details: Diabetes (New York, N.Y.), Vol.66(7), pp.2019-2032
Publisher: Amer Diabetes Assoc
Number of pages: 14
Date published: 01/07/2017
Grant note: HHSN 268201300046C; HHSN 268201300047C; HHSN 268201300048C; HHSN 268201300049C; HHSN 268201300050C; HHSN 268201000029C; HHSN 261200800001E / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Uppsala University Hospital SP/04/002 / British Heart Foundation health care center in Vaasa Singapore National Research Foundation; National Research Foundation, Singapore Finska Lakaresallskapet European Research Council; European Research Council (ERC) Pahlssons Foundation G0601261; G0900747-91070; G0601966; G0700931 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 2004310 / Directorate C-Public Health
Identifiers: 99929022602346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

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