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Nat Commun. 2018 Jan 22;9(1):321. doi: 10.1038/s41467-017-02380-9.

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

Author information

1
Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034, Barcelona, Spain.
2
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
3
Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain.
4
Section of Epigenomics and Disease, Department of Medicine, Imperial College London, London, W12 0NN, UK.
5
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
6
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
7
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain.
8
Computer Sciences Department, Barcelona Supercomputing Center (BSC-CNS), 08034, Barcelona, Spain.
9
Department of Epidemiology Research, Statens Serum Institut, 2300, Copenhagen, Denmark.
10
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02116, USA.
11
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
12
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain.
13
CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain.
14
Universitat Pompeu Fabra (UPF), 08003, Barcelona, Spain.
15
Artificial Intelligence Research Institute (IIIA), Spanish Council for Scientific Research (CSIC), 28006, Madrid, Spain.
16
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
17
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
18
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
19
Department of Molecular Biology, Harvard Medical School, Boston, MA, 02114, USA.
20
Research Centre for Prevention and Health, Capital Region of Denmark, DK-2600, Glostrup, Denmark.
21
Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark.
22
Faculty of Medicine, University of Aalborg, DK-9220, Aalborg East, Denmark.
23
Department of Clinical Experimental Research, Rigshospitalet, Glostrup, 2100, Copenhagen, Denmark.
24
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark.
25
Steno Diabetes Center, 2820, Gentofte, Denmark.
26
National Institute of Public Health, Southern Denmark University, DK-5230, Odense M, Denmark.
27
Department of Public Health, Aarhus University, DK-8000, Aarhus C, Denmark.
28
Danish Diabetes Academy, DK-5000, Odense C, Denmark.
29
Medical department, Lillebaelt Hospital, 7100, Vejle, Denmark.
30
Department of Clinical Biochemistry, Lillebaelt Hospital, 7100, Vejle, Denmark.
31
Institute of Regional Health Research, University of Southern Denmark, DK-5230, Odense, Denmark.
32
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
33
Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
34
Faculty of Health Sciences, University of Southern Denmark, DK-5230, Odense M, Denmark.
35
Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034, Barcelona, Spain. mercader@broadinstitute.org.
36
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. mercader@broadinstitute.org.
37
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. mercader@broadinstitute.org.
38
Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034, Barcelona, Spain. david.torrents@bsc.es.
39
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain. david.torrents@bsc.es.

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.

PMID:
29358691
PMCID:
PMC5778074
DOI:
10.1038/s41467-017-02380-9
[Indexed for MEDLINE]
Free PMC Article

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