RT Journal Article
SR Electronic
T1 A comprehensive reanalysis of publicly available GWAS datasets reveals an X chromosome rare regulatory variant associated with high risk for type 2 diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 112219
DO 10.1101/112219
A1 Sílvia Bonás-Guarch
A1 Marta Guindo-Martínez
A1 Irene Miguel-Escalada
A1 Niels Grarup
A1 David Sebastian
A1 Elias Rodriguez-Fos
A1 Friman Sánchez
A1 Mercé Planas-Félix
A1 Paula Cortes-Sánchez
A1 Santi González
A1 Pascal Timshel
A1 Tune H Pers
A1 Claire C. Morgan
A1 Ignasi Moran
A1 Juan R González
A1 Ehm A. Andersson
A1 Carlos Díaz
A1 Rosa M. Badia
A1 Miriam Udler
A1 Jason Flannick
A1 Torben Jørgensen
A1 Allan Linneberg
A1 Marit E. Jørgensen
A1 Daniel R. Witte
A1 Cramer Christensen
A1 Ivan Brandslund
A1 Emil V. Appel
A1 Robert A. Scott
A1 Jian’an Luan
A1 Claudia Langenberg
A1 Nicholas J. Wareham
A1 InterAct Consortium
A1 The SIGMA T2D consortium
A1 Oluf Pedersen
A1 Antonio Zorzano
A1 Jose C Florez
A1 Torben Hansen
A1 Jorge Ferrer
A1 Josep Maria Mercader
A1 David Torrents
YR 2017
UL http://biorxiv.org/content/early/2017/04/04/112219.abstract
AB 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.