Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

• Main Authors: Bonàs-Guarch, Sílvia, Guindo-Martínez, Marta, Miguel-Escalada, Irene, Grarup, Niels, Sebastian, David, Rodriguez-Fos, Elias, Sánchez, Friman, Planas-Fèlix, Mercè, Cortes-Sánchez, Paula, González, Santi, Timshel, Pascal, Pers, Tune H, Morgan, Claire C, Moran, Ignasi, Atla, Goutham, González, Juan R, Puiggros, Montserrat, Martí, Jonathan, Andersson, Ehm A, Díaz, Carlos, Badia, Rosa M, Udler, Miriam, Leong, Aaron, Kaur, Varindepal, Flannick, Jason, Jørgensen, Torben, Linneberg, Allan, Jørgensen, Marit E, Witte, Daniel R, Christensen, Cramer, Brandslund, Ivan, Appel, Emil V, Scott, Robert A, Luan, Jian'an, Langenberg, Claudia, Wareham, Nicholas J, Pedersen, Oluf, Zorzano, Antonio, Florez, Jose C, Hansen, Torben, Ferrer, Jorge, Mercader, Josep Maria, Torrents, David
• Format: Journal Article
• Language: English
• Published: Springer Science and Business Media LLC 22.01.2018; Nat Commun; http://dx.doi.org/10.1038/s41467-017-02380-9
• Subjects: Alleles; Chromosomes, Human, X; Gene Regulatory Networks; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Insulin Resistance; Male; Models, Genetic; Polymorphism, Single Nucleotide; Risk Factors
• DOI: 10.17863/CAM.21898

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, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 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.