TY - JOUR 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 DO - 10.1101/112219 SP - 112219 AU - Sílvia Bonás-Guarch AU - Marta Guindo-Martínez AU - Irene Miguel-Escalada AU - Niels Grarup AU - David Sebastian AU - Elias Rodriguez-Fos AU - Friman Sánchez AU - Mercé Planas-Félix AU - Paula Cortes-Sánchez AU - Santi González AU - Pascal Timshel AU - Tune H Pers AU - Claire C. Morgan AU - Ignasi Moran AU - Juan R González AU - Ehm A. Andersson AU - Carlos Díaz AU - Rosa M. Badia AU - Miriam Udler AU - Jason Flannick AU - Torben Jørgensen AU - Allan Linneberg AU - Marit E. Jørgensen AU - Daniel R. Witte AU - Cramer Christensen AU - Ivan Brandslund AU - Emil V. Appel AU - Robert A. Scott AU - Jian’an Luan AU - Claudia Langenberg AU - Nicholas J. Wareham AU - InterAct Consortium AU - The SIGMA T2D consortium AU - Oluf Pedersen AU - Antonio Zorzano AU - Jose C Florez AU - Torben Hansen AU - Jorge Ferrer AU - Josep Maria Mercader AU - David Torrents Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/04/112219.abstract N2 - 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. ER -