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 Maegi; Rona J. Strawbridge; Emil Rehnberg; Stefan Gustafsson; Stavroula Kanoni; Laura J. Rasmussen-Torvik; Loic 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; Han Chen; Toshiko Tanaka; Hanneke Jansen; Albertine J. Oldehinkel; Marcel Bruinenberg; Stephan J. L. Bakker; Meena Kumari; Christian Herder; Pim van der Harst; DIAbet Genetics Replication

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 Maegi, Rona J. Strawbridge, Emil Rehnberg, Stefan Gustafsson, Stavroula Kanoni, Laura J. Rasmussen-Torvik, Loic 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, Han Chen, Toshiko Tanaka, Hanneke Jansen, Albertine J. Oldehinkel, Marcel Bruinenberg, Stephan J. L. Bakker, Meena Kumari, Christian Herder, Pim van der Harst, DIAbet Genetics Replication

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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.

Originele taal-2	English
Pagina's (van-tot)	991-+
Aantal pagina's	18
Tijdschrift	Nature Genetics
Volume	44
Nummer van het tijdschrift	9
DOI's	https://doi.org/10.1038/ng.2385
Status	Published - sep.-2012

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Scott, R. A., Lagou, V., Welch, R. P., Wheeler, E., Montasser, M. E., Luan, J., Maegi, 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., ... DIAbet Genetics Replication (2012). Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nature Genetics, 44(9), 991-+. https://doi.org/10.1038/ng.2385

@article{0acb07cf2dd64c0ebd2519d3bd76a905,

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.",

keywords = "GENOME-WIDE ASSOCIATION, BODY-MASS INDEX, KLOTHO GENE POLYMORPHISMS, BINDING-PROTEIN-ALPHA, INSULIN-RESISTANCE, GLUCOSE-METABOLISM, SUSCEPTIBILITY LOCI, KAPPA-B, CARDIOVASCULAR-DISEASE, SKELETAL-MUSCLE",

author = "Scott, {Robert A.} and Vasiliki Lagou and Welch, {Ryan P.} and Eleanor Wheeler and Montasser, {May E.} and Jian'an Luan and Reedik Maegi and Strawbridge, {Rona J.} and Emil Rehnberg and Stefan Gustafsson and Stavroula Kanoni and Rasmussen-Torvik, {Laura J.} and Loic 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 {St Pourcain}, Beate 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 Han Chen and Toshiko Tanaka and Hanneke Jansen and Oldehinkel, {Albertine J.} and Marcel Bruinenberg and Bakker, {Stephan J. L.} and Meena Kumari and Christian Herder and {van der Harst}, Pim and {DIAbet Genetics Replication}",

year = "2012",

month = sep,

doi = "10.1038/ng.2385",

language = "English",

volume = "44",

pages = "991--+",

journal = "Nature Genetics",

publisher = "Nature Publishing Group",

number = "9",

}

Scott, RA, Lagou, V, Welch, RP, Wheeler, E, Montasser, ME, Luan, J, Maegi, 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, St Pourcain, B, Wu, Y, Andrews, JS, Hui, J, Bielak, LF, Zhao, W, Horikoshi, M, Navarro, P, Isaacs, A, Chen, H, Tanaka, T, Jansen, H, Oldehinkel, AJ , Bruinenberg, M , Bakker, SJL, Kumari, M, Herder, C, van der Harst, P & DIAbet Genetics Replication 2012, 'Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways', Nature Genetics, vol. 44, nr. 9, blz. 991-+. https://doi.org/10.1038/ng.2385

TY - JOUR

T1 - Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

AU - Scott, Robert A.

AU - Lagou, Vasiliki

AU - Welch, Ryan P.

AU - Wheeler, Eleanor

AU - Montasser, May E.

AU - Luan, Jian'an

AU - Maegi, Reedik

AU - Strawbridge, Rona J.

AU - Rehnberg, Emil

AU - Gustafsson, Stefan

AU - Kanoni, Stavroula

AU - Rasmussen-Torvik, Laura J.

AU - Yengo, Loic

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 - St Pourcain, Beate

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 - Chen, Han

AU - Tanaka, Toshiko

AU - Jansen, Hanneke

AU - Oldehinkel, Albertine J.

AU - Bruinenberg, Marcel

AU - Bakker, Stephan J. L.

AU - Kumari, Meena

AU - Herder, Christian

AU - van der Harst, Pim

AU - DIAbet Genetics Replication

PY - 2012/9

Y1 - 2012/9

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.

KW - GENOME-WIDE ASSOCIATION

KW - BODY-MASS INDEX

KW - KLOTHO GENE POLYMORPHISMS

KW - BINDING-PROTEIN-ALPHA

KW - INSULIN-RESISTANCE

KW - GLUCOSE-METABOLISM

KW - SUSCEPTIBILITY LOCI

KW - KAPPA-B

KW - CARDIOVASCULAR-DISEASE

KW - SKELETAL-MUSCLE

U2 - 10.1038/ng.2385

DO - 10.1038/ng.2385

M3 - Article

VL - 44

SP - 991-+

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

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