A Comprehensive Reanalysis Of Publicly Available GWAS Datasets Reveals An X Chromosome Rare Regulatory Variant Associated With High Risk For Type 2 Diabetes.
By
Sílvia Bonás-Guarch,
Marta Guindo-Martínez,
Irene Miguel-Escalada,
Niels Grarup,
David Sebastian,
Elias Rodriguez-Fos,
Friman Sánchez,
Mercé Planas-Félix,
Paula Cortes-Sánchez,
Santi González,
Pascal Timshel,
Tune H. Pers,
Claire C Morgan,
Ignasi Moran,
Juan R Gonzalez,
Ehm A Andersson,
Carlos Díaz,
Rosa M. Badia,
Miriam Udler,
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,
InterAct Consortium,
The SIGMA T2D consortium,
Oluf Pedersen,
Antonio Zorzano,
Jose C. Florez,
Torben Hansen,
Jorge Ferrer,
Josep Maria Mercader,
David Torrents
Posted 02 Apr 2017
bioRxiv DOI: 10.1101/112219
(published DOI: 10.1038/s41467-017-02380-9)
The reanalysis of publicly available GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics and pathophysiology of complex diseases. We demonstrate this by gathering and reanalyzing public type 2 diabetes (T2D) GWAS data for 70,127 subjects, using an innovative imputation and association strategy based on multiple reference panels (1000G and UK10K). This approach led us replicate and fine map 50 known T2D loci, and identify seven novel associated regions: five driven by common variants in or near LYPLAL1, NEUROG3, CAMKK2, ABO and GIP genes; one by a low frequency variant near EHMT2; and one driven by a rare variant in chromosome Xq23, associated with a 2.7-fold increased risk for T2D in males, and located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a known modulator of insulin sensitivity. We further show that the risk T allele reduces binding of a nuclear protein, resulting in increased enhancer activity in muscle cells. Beyond providing novel insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel analytical approaches.
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