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 () and David Torrents ()
Additional contact information
Sílvia Bonàs-Guarch: Joint BSC-CRG-IRB Research Program in Computational Biology
Marta Guindo-Martínez: Joint BSC-CRG-IRB Research Program in Computational Biology
Irene Miguel-Escalada: Institut d’Investigacions August Pi i Sunyer (IDIBAPS)
Niels Grarup: University of Copenhagen
David Sebastian: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)
Elias Rodriguez-Fos: Joint BSC-CRG-IRB Research Program in Computational Biology
Friman Sánchez: Joint BSC-CRG-IRB Research Program in Computational Biology
Mercè Planas-Fèlix: Joint BSC-CRG-IRB Research Program in Computational Biology
Paula Cortes-Sánchez: Joint BSC-CRG-IRB Research Program in Computational Biology
Santi González: Joint BSC-CRG-IRB Research Program in Computational Biology
Pascal Timshel: University of Copenhagen
Tune H. Pers: University of Copenhagen
Claire C. Morgan: Imperial College London
Ignasi Moran: Imperial College London
Goutham Atla: Institut d’Investigacions August Pi i Sunyer (IDIBAPS)
Juan R. González: Centre for Research in Environmental Epidemiology (CREAL)
Montserrat Puiggros: Joint BSC-CRG-IRB Research Program in Computational Biology
Jonathan Martí: Barcelona Supercomputing Center (BSC-CNS)
Ehm A. Andersson: University of Copenhagen
Carlos Díaz: Barcelona Supercomputing Center (BSC-CNS)
Rosa M. Badia: Barcelona Supercomputing Center (BSC-CNS)
Miriam Udler: Broad Institute of Harvard and MIT
Aaron Leong: Massachusetts General Hospital
Varindepal Kaur: Massachusetts General Hospital
Jason Flannick: Broad Institute of Harvard and MIT
Torben Jørgensen: Capital Region of Denmark
Allan Linneberg: Capital Region of Denmark
Marit E. Jørgensen: Steno Diabetes Center
Daniel R. Witte: Aarhus University
Cramer Christensen: Lillebaelt Hospital
Ivan Brandslund: Lillebaelt Hospital
Emil V. Appel: University of Copenhagen
Robert A. Scott: Cambridge Biomedical Campus
Jian’an Luan: Cambridge Biomedical Campus
Claudia Langenberg: Cambridge Biomedical Campus
Nicholas J. Wareham: Cambridge Biomedical Campus
Oluf Pedersen: University of Copenhagen
Antonio Zorzano: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)
Jose C Florez: Broad Institute of Harvard and MIT
Torben Hansen: University of Copenhagen
Jorge Ferrer: Institut d’Investigacions August Pi i Sunyer (IDIBAPS)
Josep Maria Mercader: Joint BSC-CRG-IRB Research Program in Computational Biology
David Torrents: Joint BSC-CRG-IRB Research Program in Computational Biology

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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, rs146662075, associated with a twofold increased risk for T2D in males. rs146662075 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.

Date: 2018
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DOI: 10.1038/s41467-017-02380-9

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