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Hum Mol Genet. 2016 May 15;25(10):2070-2081. Epub 2016 Feb 23.

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

Author information

1
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
2
Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain, Josep Carreras Leukaemia Research Institute, Badalona, Spain, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
3
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
4
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
5
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
6
Saw Swee Hock School of Public Health.
7
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA, Saw Swee Hock School of Public Health.
8
Department of Diabetes and Endocrinology, JR Tokyo General Hospital, Tokyo, Japan.
9
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine and.
10
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
11
Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, UK, Department of Epidemiology and Biostatistics.
12
Interdisciplinary Program in Bioinformatics and.
13
Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
14
Genomics and Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India.
15
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
16
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
17
Integrative Genomics and Modelization of Metabolic Diseases CNRS UMR8199, Lille Institute of Biology, E.G.I.D - FR3508 European Genomics Institute of Diabetes, Lille, France.
18
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
19
Department of Medicine and Therapeutics.
20
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA, Department of Genetics and Department of Medicine, Harvard Medical School, Boston, MA, USA, Department of Molecular Biology, Diabetes Research Center (Diabetes Unit), Department of Medicine.
21
Departments of Medicine and Human Genetics, University of Chicago, Chicago, IL, USA.
22
Department of Genetics, Texas Biomedical Research Institute, Houston, TX, USA.
23
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA, Diabetes Research Center (Diabetes Unit), Department of Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA, Center for Human Genetic Research, Department of Medicine, and.
24
Blood Systems Research Institute, San Francisco, CA, USA, Department of Laboratory Medicine and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
25
Department of Natural Science, University of Haifa, Haifa, Israel, Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, USA.
26
Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
27
Department of Genomics of Common Disease, School of Public Health, Integrative Genomics and Modelization of Metabolic Diseases CNRS UMR8199, Lille Institute of Biology, E.G.I.D - FR3508 European Genomics Institute of Diabetes, Lille, France.
28
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
29
Genomics and Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
30
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA, National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
31
Department of Medicine, Harvard Medical School, Boston, MA, USA, General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
32
Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea.
33
Interdisciplinary Program in Bioinformatics and Department of Statistics, Seoul National University, Seoul, Republic of Korea.
34
Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, UK, National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College Healthcare NHS Trust, and.
35
Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, UK, Department of Epidemiology and Biostatistics, Imperial College Healthcare NHS Trust, and.
36
Department of Biostatistics and Epidemiology, Center for Non-Communicable Diseases, University of Pennsylvania, Philadelphia, PA, USA.
37
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine and Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo, Japan.
38
Saw Swee Hock School of Public Health, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore, Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore.
39
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
40
School of Medicine, Vanderbilt University, Nashville, TN, USA.
41
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain, Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain, Department of Medicine, Imperial College London, London, UK.
42
Saw Swee Hock School of Public Health, Life Sciences Institute and Department of Statistics and Applied Probability, National University of Singapore, Singapore.
43
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK, Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK and.
44
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK, Department of Biostatistics, University of Liverpool, Liverpool, UK a.p.morris@liverpool.ac.uk.

Abstract

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

PMID:
26911676
PMCID:
PMC5062576
DOI:
10.1093/hmg/ddw048
[Indexed for MEDLINE]
Free PMC Article

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