Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

Sílvia Bonàs-Guarch; Marta Guindo-Martínez; Irene Miguel-Escalada; Niels Grarup; David Sebastian; Elias Rodriguez-Fos; Friman Sánchez; Mercè Planas-Fèlix; Paula Cortes-Sánchez; Santi González; Pascal Timshel; Tune H Pers; Claire C Morgan; Ignasi Moran; Goutham Atla; Juan R González; Montserrat Puiggros; Jonathan Martí; Ehm A Andersson; Carlos Díaz; Rosa M Badia; Miriam Udler; Aaron Leong; Varindepal Kaur; Jason Flannick; Torben Jørgensen; Allan Linneberg; Marit E Jørgensen; Daniel R Witte; Cramer Christensen; Ivan Brandslund; Emil V Appel; Robert A Scott; Jian'an Luan; Claudia Langenberg; Nicholas J Wareham; Oluf Pedersen; Antonio Zorzano; Jose C Florez; Torben Hansen; Jorge Ferrer; Josep Maria Mercader; David Torrents

doi:10.1038/s41467-017-02380-9

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

Sílvia Bonàs-Guarch, Marta Guindo-Martínez, Irene Miguel-Escalada, Niels Grarup, David Sebastian, Elias Rodriguez-Fos, Friman Sánchez, Mercè Planas-Fèlix, Paula Cortes-Sánchez, Santi González, Pascal Timshel, Tune H Pers, Claire C Morgan, Ignasi Moran, Goutham Atla, Juan R González, Montserrat Puiggros, Jonathan Martí, Ehm A Andersson, Carlos DíazRosa M Badia, Miriam Udler, Aaron Leong, Varindepal Kaur, Jason Flannick, Torben Jørgensen, Allan Linneberg, Marit E Jørgensen, Daniel R Witte, Cramer Christensen, Ivan Brandslund, Emil V Appel, Robert A Scott, Jian'an Luan, Claudia Langenberg, Nicholas J Wareham, Oluf Pedersen, Antonio Zorzano, Jose C Florez, Torben Hansen, Jorge Ferrer, Josep Maria Mercader, David Torrents

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Abstract

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

Original language	English
Article number	321
Journal	Nature Communications
Volume	9
Number of pages	14
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-017-02380-9
Publication status	Published - 1 Dec 2018

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetesFinal published version, 1.24 MBLicence: CC BY

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Bonàs-Guarch, S., Guindo-Martínez, M., Miguel-Escalada, I., Grarup, N., Sebastian, D., Rodriguez-Fos, E., Sánchez, F., Planas-Fèlix, M., Cortes-Sánchez, P., González, S., Timshel, P., Pers, T. H., Morgan, C. C., Moran, I., Atla, G., González, J. R., Puiggros, M., Martí, J., Andersson, E. A., ... Torrents, D. (2018). Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes. Nature Communications, 9, [321]. https://doi.org/10.1038/s41467-017-02380-9

Bonàs-Guarch, S, Guindo-Martínez, M, Miguel-Escalada, I, Grarup, N, Sebastian, D, Rodriguez-Fos, E, Sánchez, F, Planas-Fèlix, M, Cortes-Sánchez, P, González, S, Timshel, P, Pers, TH, Morgan, CC, Moran, I, Atla, G, González, JR, Puiggros, M, Martí, J, Andersson, EA, Díaz, C, Badia, RM, Udler, M, Leong, A, Kaur, V, Flannick, J, Jørgensen, T, Linneberg, A, Jørgensen, ME, Witte, DR, Christensen, C, Brandslund, I, Appel, EV, Scott, RA, Luan, J, Langenberg, C, Wareham, NJ, Pedersen, O, Zorzano, A, Florez, JC, Hansen, T, Ferrer, J, Mercader, JM & Torrents, D 2018, 'Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes', Nature Communications, vol. 9, 321. https://doi.org/10.1038/s41467-017-02380-9

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abstract = "The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.",

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AU - Bonàs-Guarch, Sílvia

AU - Guindo-Martínez, Marta

AU - Miguel-Escalada, Irene

AU - Grarup, Niels

AU - Sebastian, David

AU - Rodriguez-Fos, Elias

AU - Sánchez, Friman

AU - Planas-Fèlix, Mercè

AU - Cortes-Sánchez, Paula

AU - González, Santi

AU - Timshel, Pascal

AU - Pers, Tune H

AU - Morgan, Claire C

AU - Moran, Ignasi

AU - Atla, Goutham

AU - González, Juan R

AU - Puiggros, Montserrat

AU - Martí, Jonathan

AU - Andersson, Ehm A

AU - Díaz, Carlos

AU - Badia, Rosa M

AU - Udler, Miriam

AU - Leong, Aaron

AU - Kaur, Varindepal

AU - Flannick, Jason

AU - Jørgensen, Torben

AU - Linneberg, Allan

AU - Jørgensen, Marit E

AU - Witte, Daniel R

AU - Christensen, Cramer

AU - Brandslund, Ivan

AU - Appel, Emil V

AU - Scott, Robert A

AU - Luan, Jian'an

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Pedersen, Oluf

AU - Zorzano, Antonio

AU - Florez, Jose C

AU - Hansen, Torben

AU - Ferrer, Jorge

AU - Mercader, Josep Maria

AU - Torrents, David

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

AB - The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

KW - Journal Article

UR - https://www.nature.com/articles/s41467-018-04170-3.pdf

U2 - 10.1038/s41467-017-02380-9

DO - 10.1038/s41467-017-02380-9

M3 - Journal article

C2 - 29358691

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 321

ER -

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

Abstract

Keywords

UN SDGs

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