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

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Open Access

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

Author(s) -

Alisa K. Manning,

Heather M. Highland,

Jessica A. Gasser,

Xueling Sim,

Taru Tukiainen,

Pierre Fontanillas,

Niels Grarup,

Manuel A. Rivas,

Anubha Mahajan,

Adam E. Locke,

Pablo Cingolani,

Tune H. Pers,

Ana Viñuela,

Andrew Brown,

Ying Wu,

Jason Flannick,

Christian Fuchsberger,

Eric R. Gamazon,

Kyle J. Gaulton,

Hae Kyung Im,

Tanya M. Teslovich,

Thomas W. Blackwell,

Jette BorkJensen,

Noël P. Burtt,

Yuhui Chen,

Todd J. Green,

Christopher Hartl,

Hyun Min Kang,

Ashish Kumar,

Claes Ladenvall,

Clement Ma,

Loukas Moutsianas,

Richard D. Pearson,

John R. B. Perry,

Nigel W. Rayner,

Neil R. Robertson,

Laura J. Scott,

Martijn van de Bunt,

Johan G. Eriksson,

Antti Jula,

Seppo Koskinen,

Terho Lehtimäki,

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 Jackson,

Goo Jun,

Johanne Marie Justesen,

Massimo Mangino,

Jacquelyn Murphy,

Matt J. Neville,

Robert C. Onofrio,

Kerrin S. Small,

Heather M. Stringham,

Joseph Trakalo,

Eric Banks,

Jason Carey,

Mauricio O. Carneiro,

Mark A. DePristo,

Yossi Farjoun,

Timothy R. Fennell,

Jacqueline I. Goldstein,

George Grant,

Martin Hrabé de Angelis,

Jared Maguire,

Benjamin M. Neale,

Ryan Poplin,

Shaun Purcell,

Thomas Schwarzmayr,

Khalid Shakir,

Joshua D. Smith,

Tim M. Strom,

Thomas Wieland,

Jaana Lindström,

Ivan Brandslund,

Cramer Christensen,

Gabriela Surdulescu,

Timo A. Lakka,

Alex S. F. Doney,

Peter M. Nilsson,

Nicholas J. Wareham,

Claudia Langenberg,

Tibor V. Varga,

Paul W. Franks,

Olov Rolandsson,

Anders H. Rosengren,

Vidya S. Farook,

Farook Thameem,

Sobha Puppala,

Satish Kumar,

Donna M. Lehman,

Christopher P. Jenkinson,

Joanne E. Curran,

Daniel E. Hale,

Sharon P. Fowler,

Rector Arya,

Ralph A. DeFronzo,

Hanna E. Abboud,

AnnChristine Syvänen,

Andrew A. Hicks,

Nicholette D. Palmer,

Maggie C. Y. Ng,

Donald W. Bowden,

Barry I. Freedman,

Tõnu Esko,

Reedik Mägi,

Lili Milani,

Evelin Mihailov,

Andres Metspalu,

Narisu Narisu,

Leena Kinnunen,

Lori L. Bonnycastle,

Amy J. Swift,

Dorota Pasko,

Andrew R. Wood,

João Fadista,

Toni I. Pollin,

Nir Barzilai,

Gil Atzmon,

Benjamin Gläser,

Barbara Thorand,

Konstantin Strauch,

Annette Peters,

Michael Roden,

Martina MüllerNurasyid,

Liming Liang,

Jennifer Kriebel,

Thomas Illig,

Harald Grallert,

Christian Gieger,

Christa Meisinger,

Lars Lannfelt,

Solomon K. Musani,

Michael Griswold,

Herman A. Taylor,

Gregory Wilson,

Adolfo Correa,

Heikki Oksa,

William R. Scott,

Uzma Afzal,

Han Sun,

Marie Loh,

John C. Chambers,

Jobanpreet Sehmi,

Jaspal S. Kooner,

Benjamin Lehne,

Yoon Shin Cho,

JongYoung Lee,

BokGhee Han,

Annemari Käräjämäki,

Qibin Qi,

Lu Qi,

Jinyan Huang,

Frank B. Hu,

Olle Melander,

Marju OrhoMelander,

Jennifer E. Below,

David Aguilar,

Tien Yin Wong,

Jianjun Liu,

Chiea Chuen Khor,

Kee Seng Chia,

Wei Yen Lim,

ChingYu Cheng,

Edmund Chan,

E Shyong Tai,

Tin Aung,

Allan Linneberg,

Bo Isomaa,

Thomas Meitinger,

Jaakko Tuomilehto,

Liisa Hakaste,

Jasmina Kravić,

Marit E. Jørgensen,

Torsten Lauritzen,

Panos Deloukas,

Kathleen Stirrups,

Katharine R. Owen,

Andrew Farmer,

Timothy M. Frayling,

Stephen O’Rahilly,

Mark Walker,

J Levý,

Dylan Hodgkiss,

Andrew T. Hattersley,

Teemu Kuulasmaa,

Alena Stančáková,

Inês Barroso,

Dwaipayan Bharadwaj,

Juliana C.N. Chan,

Giriraj R. Chandak,

Mark J. Daly,

Peter Donnelly,

Shah B. Ebrahim,

Paul Elliott,

Tasha E. Fingerlin,

Philippe Froguel,

Cheng Hu,

Weiping Jia,

Ronald C.W.,

Gilean McVean,

Taesung Park,

Dorairaj Prabhakaran,

Manjinder S. Sandhu,

James Scott,

Robert Sladek,

Nikhil Tandon,

Yik Ying Teo,

Eleftheria Zeggini,

Richard M. Watanabe,

Heikki A. Koistinen,

Y. Antero Kesäniemi,

Matti Uusitupa,

Timothy D. Spector,

Veikko Salomaa,

Rainer Rauramaa,

Inga Prokopenko,

Andrew D. Morris,

Richard N. Bergman,

Francis S. Collins,

Lars Lind,

Erik Ingelsson,

Fredrik Karpe,

Leif Groop,

Torben Jørgensen,

Torben Hansen,

Oluf Pedersen,

Johanna Kuusisto,

Gonçalo R. Abecasis,

Graeme I. Bell,

John Blangero,

Nancy J. Cox,

Ravindranath Duggirala,

Mark Seielstad,

James G. Wilson,

Josée Dupuis,

Samuli Ripatti,

Craig L. Hanis,

José C. Florez,

Karen L. Mohlke,

James B. Meigs,

Markku Laakso,

Andrew P. Morris,

Michael Boehnke,

David Altshuler,

Mark I. McCarthy,

Anna L. Gloyn,

Cecilia M. Lindgren

Publication year - 2017

Publication title -

diabetes

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 3.219

H-Index - 330

eISSN - 1939-327X

pISSN - 0012-1797

DOI - 10.2337/db16-1329

Subject(s) - type 2 diabetes , allele , genome wide association study , genetics , insulin , genotyping , allele frequency , exome sequencing , population , minor allele frequency , endocrinology , hnf1a , biology , medicine , diabetes mellitus , single nucleotide polymorphism , genotype , gene , mutation , environmental health

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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