Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Robert A Scott; Vasiliki Lagou; Ryan P Welch; Eleanor Wheeler; May E Montasser; Jian'an Luan; Reedik Mägi; Rona J Strawbridge; Emil Rehnberg; Stefan Gustafsson; Stavroula Kanoni; Laura J Rasmussen-Torvik; Loïc Yengo; Cecile Lecoeur; Dmitry Shungin; Serena Sanna; Carlo Sidore; Paul C D Johnson; J Wouter Jukema; Toby Johnson; Anubha Mahajan; Niek Verweij; Gudmar Thorleifsson; Jouke-Jan Hottenga; Sonia Shah; Albert V Smith; Bengt Sennblad; Christian Gieger; Perttu Salo; Markus Perola; Nicholas J Timpson; David M Evans; Beate St Pourcain; Ying Wu; Jeanette S Andrews; Jennie Hui; Lawrence F Bielak; Wei Zhao; Momoko Horikoshi; Pau Navarro; Aaron Isaacs; Jeffrey R O'Connell; Kathleen Stirrups; Veronique Vitart; Caroline Hayward; Tõnu Esko; Evelin Mihailov; Meena Kumari; George Davey Smith; Mika Kivimaki; DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium

doi:10.1038/ng.2385

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Robert A Scott, Vasiliki Lagou, Ryan P Welch, Eleanor Wheeler, May E Montasser, Jian'an Luan, Reedik Mägi, Rona J Strawbridge, Emil Rehnberg, Stefan Gustafsson, Stavroula Kanoni, Laura J Rasmussen-Torvik, Loïc Yengo, Cecile Lecoeur, Dmitry Shungin, Serena Sanna, Carlo Sidore, Paul C D Johnson, J Wouter Jukema, Toby JohnsonAnubha Mahajan, Niek Verweij, Gudmar Thorleifsson, Jouke-Jan Hottenga, Sonia Shah, Albert V Smith, Bengt Sennblad, Christian Gieger, Perttu Salo, Markus Perola, Nicholas J Timpson, David M Evans, Beate St Pourcain, Ying Wu, Jeanette S Andrews, Jennie Hui, Lawrence F Bielak, Wei Zhao, Momoko Horikoshi, Pau Navarro, Aaron Isaacs, Jeffrey R O'Connell, Kathleen Stirrups, Veronique Vitart, Caroline Hayward, Tõnu Esko, Evelin Mihailov, Meena Kumari, George Davey Smith, Mika Kivimaki, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium

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Abstract

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q <0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Original language	English
Pages (from-to)	991-1005
Number of pages	15
Journal	Nature Genetics
Volume	44
Issue number	9
DOIs	https://doi.org/10.1038/ng.2385
Publication status	Published - 2012

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B603 THE EFFECT OF COMMON DISEASE ASSOCIATED GENETIC VARIANTS ON TRANSCRIPTOMIC AND EARLY LIFE PHENOTYPES
Evans, D. (Principal Investigator)
1/09/08 → 1/09/11
Project: Research
CENTRE FOR CASUAL ANALYSES IN TRANSLATIONAL EPIDEMIOLOGY (CAiTE)
Davey Smith, G. (Principal Investigator)
1/09/07 → 1/09/13
Project: Research

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Scott, R. A., Lagou, V., Welch, R. P., Wheeler, E., Montasser, M. E., Luan, J., Mägi, R., Strawbridge, R. J., Rehnberg, E., Gustafsson, S., Kanoni, S., Rasmussen-Torvik, L. J., Yengo, L., Lecoeur, C., Shungin, D., Sanna, S., Sidore, C., Johnson, P. C. D., Jukema, J. W., ... DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium (2012). Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nature Genetics, 44(9), 991-1005. https://doi.org/10.1038/ng.2385

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title = "Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways",

abstract = "Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q <0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.",

author = "Scott, {Robert A} and Vasiliki Lagou and Welch, {Ryan P} and Eleanor Wheeler and Montasser, {May E} and Jian'an Luan and Reedik M{\"a}gi and Strawbridge, {Rona J} and Emil Rehnberg and Stefan Gustafsson and Stavroula Kanoni and Rasmussen-Torvik, {Laura J} and Lo{\"i}c Yengo and Cecile Lecoeur and Dmitry Shungin and Serena Sanna and Carlo Sidore and Johnson, {Paul C D} and Jukema, {J Wouter} and Toby Johnson and Anubha Mahajan and Niek Verweij and Gudmar Thorleifsson and Jouke-Jan Hottenga and Sonia Shah and Smith, {Albert V} and Bengt Sennblad and Christian Gieger and Perttu Salo and Markus Perola and Timpson, {Nicholas J} and Evans, {David M} and Pourcain, {Beate St} and Ying Wu and Andrews, {Jeanette S} and Jennie Hui and Bielak, {Lawrence F} and Wei Zhao and Momoko Horikoshi and Pau Navarro and Aaron Isaacs and O'Connell, {Jeffrey R} and Kathleen Stirrups and Veronique Vitart and Caroline Hayward and T{\~o}nu Esko and Evelin Mihailov and Meena Kumari and Smith, {George Davey} and Mika Kivimaki and {DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium}",

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Scott, RA, Lagou, V, Welch, RP, Wheeler, E, Montasser, ME, Luan, J, Mägi, R, Strawbridge, RJ, Rehnberg, E, Gustafsson, S, Kanoni, S, Rasmussen-Torvik, LJ, Yengo, L, Lecoeur, C, Shungin, D, Sanna, S, Sidore, C, Johnson, PCD, Jukema, JW, Johnson, T, Mahajan, A, Verweij, N, Thorleifsson, G, Hottenga, J-J, Shah, S, Smith, AV, Sennblad, B, Gieger, C, Salo, P, Perola, M, Timpson, NJ, Evans, DM, Pourcain, BS, Wu, Y, Andrews, JS, Hui, J, Bielak, LF, Zhao, W, Horikoshi, M, Navarro, P, Isaacs, A, O'Connell, JR, Stirrups, K, Vitart, V, Hayward, C, Esko, T, Mihailov, E, Kumari, M, Smith, GD, Kivimaki, M & DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium 2012, 'Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways', Nature Genetics, vol. 44, no. 9, pp. 991-1005. https://doi.org/10.1038/ng.2385

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AU - Scott, Robert A

AU - Lagou, Vasiliki

AU - Welch, Ryan P

AU - Wheeler, Eleanor

AU - Montasser, May E

AU - Luan, Jian'an

AU - Mägi, Reedik

AU - Strawbridge, Rona J

AU - Rehnberg, Emil

AU - Gustafsson, Stefan

AU - Kanoni, Stavroula

AU - Rasmussen-Torvik, Laura J

AU - Yengo, Loïc

AU - Lecoeur, Cecile

AU - Shungin, Dmitry

AU - Sanna, Serena

AU - Sidore, Carlo

AU - Johnson, Paul C D

AU - Jukema, J Wouter

AU - Johnson, Toby

AU - Mahajan, Anubha

AU - Verweij, Niek

AU - Thorleifsson, Gudmar

AU - Hottenga, Jouke-Jan

AU - Shah, Sonia

AU - Smith, Albert V

AU - Sennblad, Bengt

AU - Gieger, Christian

AU - Salo, Perttu

AU - Perola, Markus

AU - Timpson, Nicholas J

AU - Evans, David M

AU - Pourcain, Beate St

AU - Wu, Ying

AU - Andrews, Jeanette S

AU - Hui, Jennie

AU - Bielak, Lawrence F

AU - Zhao, Wei

AU - Horikoshi, Momoko

AU - Navarro, Pau

AU - Isaacs, Aaron

AU - O'Connell, Jeffrey R

AU - Stirrups, Kathleen

AU - Vitart, Veronique

AU - Hayward, Caroline

AU - Esko, Tõnu

AU - Mihailov, Evelin

AU - Kumari, Meena

AU - Smith, George Davey

AU - Kivimaki, Mika

AU - DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium

PY - 2012

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N2 - Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q <0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

AB - Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q <0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

U2 - 10.1038/ng.2385

DO - 10.1038/ng.2385

M3 - Article (Academic Journal)

C2 - 22885924

SN - 1546-1718

VL - 44

SP - 991

EP - 1005

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Abstract

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B603 THE EFFECT OF COMMON DISEASE ASSOCIATED GENETIC VARIANTS ON TRANSCRIPTOMIC AND EARLY LIFE PHENOTYPES

CENTRE FOR CASUAL ANALYSES IN TRANSLATIONAL EPIDEMIOLOGY (CAiTE)

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