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Nat Genet. 2018 Nov;50(11):1505-1513. doi: 10.1038/s41588-018-0241-6. Epub 2018 Oct 8.

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Mahajan A1,2, Taliun D3, Thurner M4,5, Robertson NR4,5, Torres JM4, Rayner NW4,5,6, Payne AJ4, Steinthorsdottir V7, Scott RA8, Grarup N9, Cook JP10, Schmidt EM3, Wuttke M11, Sarnowski C12, Mägi R13, Nano J14, Gieger C15,16, Trompet S17,18, Lecoeur C19, Preuss MH20, Prins BP6, Guo X21, Bielak LF22, Below JE23, Bowden DW24,25,26, Chambers JC27,28,29,30,31, Kim YJ32, Ng MCY24,25,26, Petty LE23, Sim X33, Zhang W27,28, Bennett AJ5, Bork-Jensen J9, Brummett CM34, Canouil M19, Ec Kardt KU35, Fischer K13, Kardia SLR22, Kronenberg F36, Läll K13,37, Liu CT12, Locke AE38,39, Luan J8, Ntalla I40, Nylander V5, Schönherr S36, Schurmann C20, Yengo L19, Bottinger EP20, Brandslund I41,42, Christensen C43, Dedoussis G44, Florez JC45,46,47,48, Ford I49, Franco OH14, Frayling TM50, Giedraitis V51, Hackinger S6, Hattersley AT52, Herder C16,53, Ikram MA14, Ingelsson M51, Jørgensen ME54,55, Jørgensen T56,57,58, Kriebel J15,16, Kuusisto J59, Ligthart S14, Lindgren CM4,60,61, Linneberg A56,62,63, Lyssenko V64,65, Mamakou V66, Meitinger T67,68,69, Mohlke KL70, Morris AD71,72, Nadkarni G73, Pankow JS74, Peters A16,69,75, Sattar N76, Stančáková A59, Strauch K77,78, Taylor KD21, Thorand B16,75, Thorleifsson G7, Thorsteinsdottir U7,79, Tuomilehto J80,81,82,83, Witte DR84,85, Dupuis J12,86, Peyser PA22, Zeggini E6, Loos RJF20,87, Froguel P19,88, Ingelsson E89,90, Lind L91, Groop L64,92, Laakso M59, Collins FS93, Jukema JW18, Palmer CNA94, Grallert H15,16,95,96, Metspalu A13, Dehghan A14,27,31, Köttgen A11, Abecasis GR3, Meigs JB45,48,97, Rotter JI21,98, Marchini J4,99, Pedersen O9, Hansen T9,100, Langenberg C8, Wareham NJ8, Stefansson K7,79, Gloyn AL4,5,101, Morris AP4,10,13, Boehnke M3, McCarthy MI102,103,104.

Author information

1
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. anubha@well.ox.ac.uk.
2
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. anubha@well.ox.ac.uk.
3
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
4
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
5
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
6
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
7
deCODE Genetics, Amgen Inc., Reykjavik, Iceland.
8
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
9
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Department of Biostatistics, University of Liverpool, Liverpool, UK.
11
Institute of Genetic Epidemiology, Department of Biometry, Epidemiology, and Medical Bioinformatics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
12
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
13
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
14
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
15
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, Neuherberg, Germany.
16
German Center for Diabetes Research (DZD), Neuherberg, Germany.
17
Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
18
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
19
CNRS-UMR8199, Lille University, Lille Pasteur Institute, Lille, France.
20
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
21
Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
22
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
23
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
24
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
25
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
26
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
27
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
28
Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UK.
29
Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
30
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
31
MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
32
Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea.
33
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
34
Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA.
35
Department of Nephrology and Medical Intensive Care and German Chronic Kidney Disease Study, Charité, Universitätsmedizin Berlin, Berlin, Germany.
36
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
37
Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia.
38
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
39
Division of Genomics & Bioinformatics, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
40
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
41
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
42
Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.
43
Medical Department, Lillebælt Hospital Vejle, Vejle, Denmark.
44
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
45
Department of Medicine, Harvard Medical School, Boston, MA, USA.
46
Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
47
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
48
Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
49
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
50
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
51
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
52
University of Exeter Medical School, University of Exeter, Exeter, UK.
53
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
54
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
55
National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark.
56
Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark.
57
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
58
Faculty of Medicine, Aalborg University, Aalborg, Denmark.
59
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
60
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
61
Big Data Institute, Li Ka Shing Centre For Health Information and Discovery, University of Oxford, Oxford, UK.
62
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.
63
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
64
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
65
Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
66
Dromokaiteio Psychiatric Hospital, National and Kapodistrian University of Athens, Athens, Greece.
67
Institute of Human Genetics, Technische Universität München, Munich, Germany.
68
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
69
DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance partner site, Munich, Germany.
70
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
71
Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK.
72
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
73
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
74
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
75
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
76
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
77
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
78
Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
79
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
80
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
81
Dasman Diabetes Institute, Dasman, Kuwait.
82
Department of Neuroscience and Preventive Medicine, Danube-University Krems, Krems, Austria.
83
Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
84
Department of Public Health, Aarhus University, Aarhus, Denmark.
85
Danish Diabetes Academy, Odense, Denmark.
86
National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.
87
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
88
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
89
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
90
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
91
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
92
Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.
93
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
94
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
95
Clinical Cooparation Group Type 2 Diabetes, Helmholtz Zentrum München, Ludwig-Maximilians-Universität, Munich, Germany.
96
Clinical Cooparation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Technical University, Munich, Germany.
97
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
98
Departments of Medicine, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
99
Department of Statistics, University of Oxford, Oxford, UK.
100
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
101
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
102
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
103
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
104
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.

Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

PMID:
30297969
PMCID:
PMC6287706
DOI:
10.1038/s41588-018-0241-6
[Indexed for MEDLINE]
Free PMC Article

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