David Torrents, Carlos Díaz, Daniel R. Witte, Allan Linneberg, David Sebastián, Tune H. Pers, Friman Sánchez, Pascal Timshel, Miriam S. Udler, Varindepal Kaur, Irene Miguel-Escalada, Oluf Pedersen, Marit E. Jørgensen, Claire Morgan, Jonathan Marti, Jason Flannick, Torben Jørgensen, Ivan Brandslund, Antonio Zorzano, Rosa M. Badia, Sílvia Bonàs-Guarch, Paula Cortes-Sánchez, Claudia Langenberg, Torben Hansen, Montserrat Puiggròs, Marta Guindo-Martínez, Jose C. Florez, Elias Rodriguez-Fos, Nicholas J. Wareham, Cramer Christensen, Juan R. González, Emil V. R. Appel, Niels Grarup, Ehm A. Andersson, Josep M. Mercader, Ignasi Moran, Jorge Ferrer, Aaron Leong, Jian'an Luan, Robert A. Scott, Mercè Planas-Fèlix, Santi González, and Goutham Atla
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., Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.