1. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
- Author
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Claire Morgan, Antonio Zorzano, Jason Flannick, Claudia Langenberg, David Torrents, Torben Hansen, Juan R. González, Tune H. Pers, Jorge Ferrer, Ehm A. Andersson, Jian'an Luan, Jose C. Florez, Ivan Brandslund, Aaron Leong, Marit E. Jørgensen, Ignasi Moran, Pascal Timshel, Robert A. Scott, Cramer Christensen, Emil V. R. Appel, Niels Grarup, Paula Cortes-Sánchez, Jonathan Marti, Varindepal Kaur, Oluf Pedersen, Santi González, Elias Rodriguez-Fos, Nicholas J. Wareham, Miriam S. Udler, Josep M. Mercader, Torben Jørgensen, Montserrat Puiggròs, Sílvia Bonàs-Guarch, Irene Miguel-Escalada, Carlos Díaz, David Sebastián, Rosa M. Badia, Daniel R. Witte, Allan Linneberg, Friman Sánchez, Mercè Planas-Fèlix, Marta Guindo-Martínez, Goutham Atla, Ministerio de Economía y Competitividad (España), European Foundation for the Study of Diabetes, Instituto de Salud Carlos III, Generalitat de Catalunya, Wellcome Trust, European Commission, Fundación 'la Caixa', National Institute for Health Research (UK), Novo Nordisk Foundation, Badia, Rosa M. [0000-0003-2941-5499], Bonàs-Guarch, Sílvia [0000-0002-2085-7488], Guindo-Martínez, Marta [0000-0002-8099-9170], Miguel-Escalada, Irene [0000-0003-3461-6404], Grarup, Niels [0000-0001-5526-1070], Rodriguez-Fos, Elias [0000-0002-2555-0178], Planas-Fèlix, Mercè [0000-0002-8267-576X], González, Santi [0000-0001-5685-4580], Morgan, Claire C [0000-0002-8191-3738], Moran, Ignasi [0000-0002-3307-7106], Puiggros, Montserrat [0000-0001-5034-7924], Linneberg, Allan [0000-0002-0994-0184], Jørgensen, Marit E [0000-0001-8356-5565], Hansen, Torben [0000-0001-8748-3831], Ferrer, Jorge [0000-0002-5959-5729], Mercader, Josep Maria [0000-0001-8494-3660], Torrents, David [0000-0002-6086-9037], Apollo - University of Cambridge Repository, Barcelona Supercomputing Center, Medical Research Council (MRC), Universitat de Barcelona, and Badia, Rosa M.
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Male ,0301 basic medicine ,Insulin Resistance/genetics ,General Physics and Astronomy ,GLUCOSE ,Technical support ,0302 clinical medicine ,Human genetics ,Risk Factors ,Gene Regulatory Networks ,lcsh:Science ,media_common ,Independent research ,RISK ,INSULIN-RESISTANCE ,Diabetis ,Genètica humana ,Genome ,Multidisciplinary ,Genetic Predisposition to Disease/genetics ,Diabetes ,Biobank ,3. Good health ,Multidisciplinary Sciences ,Research centre ,Science & Technology - Other Topics ,LOW-FREQUENCY ,DIET-INDUCED OBESITY ,Genetic data ,SUSCEPTIBILITY LOCI ,Genotype ,Science ,Library science ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Chromosomes, Human, X/genetics ,Diabetis--Diagnòstic ,Political science ,MD Multidisciplinary ,Journal Article ,Humans ,media_common.cataloged_instance ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,European union ,METAANALYSIS ,Alleles ,Chromosomes, Human, X ,Science & Technology ,Models, Genetic ,Diabetes--Diagnosis ,Extramural ,PANCREATIC-ISLETS ,General Chemistry ,030104 developmental biology ,CELLS ,Susceptibility locus ,lcsh:Q ,Insulin Resistance ,030217 neurology & neurosurgery ,Gene Regulatory Networks/genetics ,Genome-Wide Association Study ,Ciències de la salut [Àrees temàtiques de la UPC] - Abstract
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., This work has been sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III and Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR). Sílvia Bonàs was FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya). This study makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. This study also makes use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available in www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We acknowledge PRACE for awarding us to access MareNostrum supercomputer, based in Spain at Barcelona. The technical support group, particularly Pablo Ródenas and Jorge Rodríguez, from the Barcelona Supercomputing Center is gratefully acknowledged. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191. Mercè Planas-Fèlix is funded by the Obra Social Fundación la Caixa fellowship under the Severo Ochoa 2013 program. Work from Irene Miguel-Escalada, Ignasi Moran, Goutham Atla, and Jorge Ferrer was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, the Wellcome Trust (WT101033), Ministerio de Economía y Competitividad (BFU2014-54284-R) and Horizon 2020 (667191). Irene Miguel-Escalada has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement No 658145. We acknowledge Prof. Giulio Cossu (Institute of Inflammation and Repair, University of Manchester) for providing the muscle myoblast cell line. We also acknowledge the InterAct and SIGMA Type 2 Diabetes Consortia for access to the data to replicate the rs146662075 variant. A full list of the investigators of the SIGMA Type 2 Diabetes and the InterAct consortia is provided in Supplementary Notes 3 and 4. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This research has been conducted using the UK Biobank Resource (application number 16803). We also acknowledge Bianca C. Porneala, MS for his technical assistance in the collection and curation of the genotype and phenotype data from Partners Biobank. We also thank Marcin von Grotthuss for their support for uploading the summary statistics data to the Type 2 Diabetes Genetic Portal (AMP-T2D portal). Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript.
- Published
- 2018
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