@article {Bon{\'a}s-Guarch112219, author = {S{\'\i}lvia Bon{\'a}s-Guarch and Marta Guindo-Mart{\'\i}nez and Irene Miguel-Escalada and Niels Grarup and David Sebastian and Elias Rodriguez-Fos and Friman S{\'a}nchez and Merc{\'e} Planas-F{\'e}lix and Paula Cortes-S{\'a}nchez and Santi Gonz{\'a}lez and Pascal Timshel and Tune H Pers and Claire C. Morgan and Ignasi Moran and Juan R Gonz{\'a}lez and Ehm A. Andersson and Carlos D{\'\i}az and Rosa M. Badia and Miriam Udler and Jason Flannick and Torben J{\o}rgensen and Allan Linneberg and Marit E. J{\o}rgensen and Daniel R. Witte and Cramer Christensen and Ivan Brandslund and Emil V. Appel and Robert A. Scott and Jian{\textquoteright}an Luan and Claudia Langenberg and Nicholas J. Wareham and InterAct Consortium and The SIGMA T2D consortium and Oluf Pedersen and Antonio Zorzano and Jose C Florez and Torben Hansen and Jorge Ferrer and Josep Maria Mercader and David Torrents}, title = {A comprehensive reanalysis of publicly available GWAS datasets reveals an X chromosome rare regulatory variant associated with high risk for type 2 diabetes}, elocation-id = {112219}, year = {2017}, doi = {10.1101/112219}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2017/04/02/112219}, eprint = {https://www.biorxiv.org/content/early/2017/04/02/112219.full.pdf}, journal = {bioRxiv} }