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Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

Mahajan A1, Wessel J2, Willems SM3, Zhao W4, Robertson NR5,6, Chu AY7,8, Gan W5, Kitajima H5, Taliun D9, Rayner NW5,6,10, Guo X11, Lu Y12, Li M13,14, Jensen RA15, Hu Y16, Huo S16, Lohman KK17, Zhang W18,19, Cook JP20, Prins BP10, Flannick J21,22, Grarup N23, Trubetskoy VV9, Kravic J24, Kim YJ25, Rybin DV26, Yaghootkar H27, Müller-Nurasyid M28,29,30, Meidtner K31,32, Li-Gao R33, Varga TV34, Marten J35, Li J36, Smith AV37,38, An P39, Ligthart S40, Gustafsson S41, Malerba G42, Demirkan A40,43, Tajes JF5, Steinthorsdottir V44, Wuttke M45, Lecoeur C46, Preuss M12, Bielak LF47, Graff M48, Highland HM49, Justice AE48, Liu DJ50, Marouli E51, Peloso GM21,26, Warren HR51,52; ExomeBP Consortium; MAGIC Consortium; GIANT Consortium, Afaq S18, Afzal S53,54,55, Ahlqvist E24, Almgren P56, Amin N40, Bang LB57, Bertoni AG58, Bombieri C42, Bork-Jensen J23, Brandslund I59,60, Brody JA15, Burtt NP21, Canouil M46, Chen YI11, Cho YS61, Christensen C62, Eastwood SV63, Eckardt KU64, Fischer K65, Gambaro G66, Giedraitis V67, Grove ML68, de Haan HG33, Hackinger S10, Hai Y11, Han S25, Tybjærg-Hansen A54,55,69, Hivert MF70,71,72, Isomaa B73,74, Jäger S31,32, Jørgensen ME75,76, Jørgensen T55,77,78, Käräjämäki A79,80, Kim BJ25, Kim SS25, Koistinen HA81,82,83,84, Kovacs P85, Kriebel J32,86, Kronenberg F87, Läll K65,88, Lange LA89, Lee JJ4, Lehne B18, Li H16, Lin KH90, Linneberg A77,91,92, Liu CT26, Liu J40, Loh M18,93,94, Mägi R65, Mamakou V95, McKean-Cowdin R96, Nadkarni G97, Neville M6,98, Nielsen SF53,54,55, Ntalla I51, Peyser PA47, Rathmann W32,99, Rice K100, Rich SS101, Rode L53,54, Rolandsson O102, Schönherr S87, Selvin E13, Small KS103, Stančáková A104, Surendran P105, Taylor KD11, Teslovich TM9, Thorand B32,106, Thorleifsson G44, Tin A107, Tönjes A108, Varbo A53,54,55,69, Witte DR109,110, Wood AR27, Yajnik P9, Yao J11, Yengo L46, Young R105,111, Amouyel P112, Boeing H113, Boerwinkle E68,114, Bottinger EP12, Chowdhury R115, Collins FS116, Dedoussis G117, Dehghan A40,118, Deloukas P51,119, Ferrario MM120, Ferrières J121,122, Florez JC70,123,124,125, Frossard P126, Gudnason V37,38, Harris TB127, Heckbert SR15, Howson JMM115, Ingelsson M67, Kathiresan S21,123,125,128, Kee F129, Kuusisto J104, Langenberg C3, Launer LJ127, Lindgren CM5,21,130, Männistö S131, Meitinger T132,133, Melander O56, Mohlke KL134, Moitry M135,136, Morris AD137,138, Murray AD139, de Mutsert R33, Orho-Melander M140, Owen KR6,98, Perola M131,141, Peters A30,32,106, Province MA39, Rasheed A126, Ridker PM8,125, Rivadineira F40,142, Rosendaal FR33, Rosengren AH24, Salomaa V131, Sheu WH143,144,145, Sladek R146,147,148, Smith BH149, Strauch K28,150, Uitterlinden AG41,142, Varma R151, Willer CJ152,153,154, Blüher M85,108, Butterworth AS105,155, Chambers JC18,19,156, Chasman DI8,125, Danesh J105,155,157,158, van Duijn C40, Dupuis J7,26, Franco OH40, Franks PW34,102,159, Froguel P46,160, Grallert H32,86,161,162, Groop L24,141, Han BG25, Hansen T23,163, Hattersley AT164, Hayward C35, Ingelsson E36,41, Kardia SLR47, Karpe F6,98, Kooner JS19,156,165, Köttgen A45, Kuulasmaa K132, Laakso M104, Lin X16, Lind L166, Liu Y58, Loos RJF12,167, Marchini J5,168, Metspalu A65, Mook-Kanamori D33,169, Nordestgaard BG53,54,55, Palmer CNA170, Pankow JS171, Pedersen O23, Psaty BM15,172, Rauramaa R173, Sattar N174, Schulze MB31,32, Soranzo N10,155,175, Spector TD103, Stefansson K38,44, Stumvoll M176, Thorsteinsdottir U38,44, Tuomi T74,82,141,177, Tuomilehto J81,178,179,180, Wareham NJ3, Wilson JG181, Zeggini E10, Scott RA3, Barroso I10,182, Frayling TM27, Goodarzi MO183, Meigs JB184, Boehnke M9, Saleheen D4,126, Morris AP5,20,65, Rotter JI185,186, McCarthy MI187,188,189.

Author information

1
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. anubha@well.ox.ac.uk.
2
Departments of Epidemiology and Medicine, Diabetes Translational Research Center, Indiana University, Indianapolis, IN, USA.
3
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
4
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
5
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
6
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
7
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
8
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
9
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
10
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
11
Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
12
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
14
Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
15
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
16
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People's Republic of China.
17
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
18
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
19
Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UK.
20
Department of Biostatistics, University of Liverpool, Liverpool, UK.
21
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
22
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
23
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
24
Department of Clinical Sciences, Diabetes, and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
25
Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea.
26
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
27
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
28
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
29
Department of Medicine I, University Hospital Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.
30
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
31
Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
32
German Center for Diabetes Research (DZD), Neuherberg, Germany.
33
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
34
Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
35
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
36
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
37
Icelandic Heart Association, Kopavogur, Iceland.
38
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
39
Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
40
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
41
Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
42
Section of Biology and Genetics, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy.
43
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
44
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
45
Institute of Genetic Epidemiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
46
CNRS, UMR 8199, Lille University, Lille Pasteur Institute, Lille, France.
47
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
48
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
49
Human Genetics Center, University of Texas Graduate School of Biomedical Sciences at Houston, University of Texas Health Science Center at Houston, Houston, TX, USA.
50
Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA.
51
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
52
National Institute for Health Research, Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
53
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
54
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
55
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
56
Department of Clinical Sciences, Hypertension, and Cardiovascular Disease, Lund University, Malmö, Sweden.
57
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
58
Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
59
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
60
Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.
61
Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea.
62
Medical Department, Lillebælt Hospital Vejle, Vejle, Denmark.
63
Institute of Cardiovascular Science, University College London, London, UK.
64
Department of Nephrology and Medical Intensive Care, Charité, University Medicine Berlin, Berlin, Germany.
65
Estonian Genome Center, University of Tartu, Tartu, Estonia.
66
Institute of Internal and Geriatric Medicine, Università Cattolica del Sacro Cuore, Rome, Italy.
67
Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden.
68
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
69
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
70
Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
71
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA.
72
Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
73
Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland.
74
Folkhälsan Research Centre, Helsinki, Finland.
75
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
76
National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark.
77
Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark.
78
Faculty of Medicine, Aalborg University, Aalborg, Denmark.
79
Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland.
80
Diabetes Center, Vaasa Health Care Center, Vaasa, Finland.
81
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
82
Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
83
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
84
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
85
Integrated Research and Treatment (IFB) Center Adiposity Diseases, University of Leipzig, Leipzig, Germany.
86
Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
87
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
88
Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia.
89
Department of Medicine, Division of Bioinformatics and Personalized Medicine, University of Colorado Denver, Aurora, CO, USA.
90
Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan.
91
Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
92
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
93
Institute of Health Sciences, University of Oulu, Oulu, Finland.
94
Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.
95
Dromokaiteio Psychiatric Hospital, National and Kapodistrian University of Athens, Athens, Greece.
96
Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
97
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
98
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
99
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
100
Department of Biostatistics, University of Washington, Seattle, WA, USA.
101
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
102
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
103
Department of Twins Research and Genetic Epidemiology, King's College London, London, UK.
104
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
105
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
106
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
107
Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
108
Department of Medicine, University of Leipzig, Leipzig, Germany.
109
Department of Public Health, Aarhus University, Aarhus, Denmark.
110
Danish Diabetes Academy, Odense, Denmark.
111
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
112
Institut Pasteur de Lille, INSERM U1167, Université Lille Nord de France, Lille, France.
113
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
114
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
115
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
116
Genome Technology Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA.
117
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
118
MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
119
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
120
Research Centre on Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, Italy.
121
INSERM, UMR 1027, Toulouse, France.
122
Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France.
123
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
124
Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
125
Department of Medicine, Harvard Medical School, Boston, MA, USA.
126
Center for Non-Communicable Diseases, Karachi, Pakistan.
127
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, US National Institutes of Health, Bethesda, MD, USA.
128
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
129
UKCRC Centre of Excellence for Public Health (NI), Queens University of Belfast, Belfast, UK.
130
Big Data Institute, Li Ka Shing Centre For Health Information and Discovery, University of Oxford, Oxford, UK.
131
National Institute for Health and Welfare, Helsinki, Finland.
132
Institute of Human Genetics, Technische Universität München, Munich, Germany.
133
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
134
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
135
Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France.
136
Department of Public Health, University Hospital of Strasbourg, Strasbourg, France.
137
Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK.
138
Usher Institute to the Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
139
Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, UK.
140
Department of Clinical Sciences, Diabetes, and Cardiovascular Disease, Genetic Epidemiology, Lund University, Malmö, Sweden.
141
Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.
142
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
143
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
144
National Yang-Ming University, School of Medicine, Taipei, Taiwan.
145
National Defense Medical Center, School of Medicine, Taipei, Taiwan.
146
McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada.
147
Department of Human Genetics, McGill University, Montreal, QC, Canada.
148
Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC, Canada.
149
Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
150
Institute of Medical Informatics, Biometry, and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
151
USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
152
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
153
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
154
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
155
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
156
Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
157
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
158
British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK.
159
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
160
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
161
Clinical Cooperation Group Type 2 Diabetes, Helmholtz Zentrum München, Ludwig-Maximillians University Munich, Munich, Germany.
162
Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Technical University of Munich, Munich, Germany.
163
Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
164
University of Exeter Medical School, University of Exeter, Exeter, UK.
165
National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK.
166
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
167
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
168
Department of Statistics, University of Oxford, Oxford, UK.
169
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
170
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
171
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
172
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
173
Foundation for Research in Health, Exercise, and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
174
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
175
Department of Hematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
176
Divisions of Endocrinology and Nephrology, University Hospital Leipzig, Leipzig, Germany.
177
Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
178
Dasman Diabetes Institute, Dasman, Kuwait.
179
Department of Neuroscience and Preventive Medicine, Danube University Krems, Krems, Austria.
180
Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
181
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
182
Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
183
Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
184
General Medicine Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA.
185
Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA. jrotter@labiomed.org.
186
Department of Medicine, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA. jrotter@labiomed.org.
187
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
188
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
189
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.

Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

PMID:
29632382
PMCID:
PMC5898373
[Available on 2018-10-09]
DOI:
10.1038/s41588-018-0084-1

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