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Nat Genet. 2019 Mar;51(3):452-469. doi: 10.1038/s41588-018-0334-2. Epub 2019 Feb 18.

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Justice AE1,2, Karaderi T3,4, Highland HM1,5, Young KL1, Graff M1, Lu Y6,7,8, Turcot V9, Auer PL10, Fine RS11,12,13, Guo X14, Schurmann C7,8, Lempradl A15, Marouli E16, Mahajan A3, Winkler TW17, Locke AE18,19, Medina-Gomez C20,21, Esko T11,13,22, Vedantam S11,12,13, Giri A23, Lo KS9,23, Alfred T7, Mudgal P24, Ng MCY24,25, Heard-Costa NL26,27, Feitosa MF28, Manning AK11,29,30, Willems SM31, Sivapalaratnam S30,32,33, Abecasis G18,34, Alam DS35, Allison M36, Amouyel P37,38,39, Arzumanyan Z14, Balkau B40, Bastarache L41, Bergmann S42,43, Bielak LF44, Blüher M45,46, Boehnke M18, Boeing H47, Boerwinkle E5,48, Böger CA49, Bork-Jensen J50, Bottinger EP7, Bowden DW24,25,51, Brandslund I52,53, Broer L21, Burt AA54, Butterworth AS55,56, Caulfield MJ16,57, Cesana G58, Chambers JC59,60,61,62,63, Chasman DI11,64,65,66, Chen YI14, Chowdhury R55, Christensen C67, Chu AY65, Collins FS68, Cook JP69, Cox AJ24,25,70, Crosslin DS71, Danesh J55,56,72,73, de Bakker PIW74,75, Denus S9,76, Mutsert R77, Dedoussis G78, Demerath EW79, Dennis JG80, Denny JC41, Angelantonio ED55,56,73, Dörr M81,82, Drenos F83,84,85, Dubé MP9,86, Dunning AM87, Easton DF80,87, Elliott P88, Evangelou E61,89, Farmaki AE78, Feng S18, Ferrannini E90,91, Ferrieres J92, Florez JC11,29,30, Fornage M93, Fox CS27, Franks PW94,95,96, Friedrich N97, Gan W3, Gandin I98, Gasparini P99,100, Giedraitis V101, Girotto G99,100, Gorski M17,49, Grallert H102,103,104, Grarup N50, Grove ML5, Gustafsson S105, Haessler J106, Hansen T50, Hattersley AT107, Hayward C108, Heid IM17,109, Holmen OL110, Hovingh GK32, Howson JMM55, Hu Y111, Hung YJ112,113, Hveem K110,114, Ikram MA20,115,116, Ingelsson E105,117, Jackson AU18, Jarvik GP54,118, Jia Y14, Jørgensen T119,120,121, Jousilahti P122, Justesen JM50, Kahali B123,124,125,126, Karaleftheri M127, Kardia SLR44, Karpe F128,129, Kee F130, Kitajima H3, Komulainen P131, Kooner JS60,62,63,132, Kovacs P45, Krämer BK133, Kuulasmaa K122, Kuusisto J134, Laakso M134, Lakka TA131,135,136, Lamparter D42,43,137, Lange LA138, Langenberg C31, Larson EB54,139,140, Lee NR141,142, Lee WJ143,144, Lehtimäki T145,146, Lewis CE147, Li H111, Li J148, Li-Gao R77, Lin LA93, Lin X111, Lind L149, Lindström J122, Linneberg A121,150,151, Liu CT152, Liu DJ153, Luan J31, Lyytikäinen LP145,146, MacGregor S154, Mägi R22, Männistö S122, Marenne G72, Marten J108, Masca NGD155,156, McCarthy MI3,128,129, Meidtner K102,157, Mihailov E22, Moilanen L158, Moitry M159,160, Mook-Kanamori DO77,161, Morgan A99, Morris AP3,69, Müller-Nurasyid M109,162,163, Munroe PB16,57, Narisu N68, Nelson CP155,156, Neville M128,129, Ntalla I16, O'Connell JR164, Owen KR128,129, Pedersen O50, Peloso GM152, Pennell CE165,166, Perola M122,167, Perry JA164, Perry JRB31, Pers TH50,168, Ewing A80, Polasek O169,170, Raitakari OT171,172, Rasheed A173, Raulerson CK174, Rauramaa R131,135, Reilly DF175, Reiner AP106,176, Ridker PM65,66,177, Rivas MA178, Robertson NR3,128, Robino A179, Rudan I170, Ruth KS180, Saleheen D173,181, Salomaa V122, Samani NJ155,156, Schreiner PJ182, Schulze MB102,157, Scott RA31, Segura-Lepe M61, Sim X18,183, Slater AJ184,185, Small KS186, Smith BH187,188, Smith JA44, Southam L3,72, Spector TD186, Speliotes EK123,124,125, Stefansson K189,190, Steinthorsdottir V189, Stirrups KE16,33, Strauch K109,191, Stringham HM18, Stumvoll M45,46, Sun L111, Surendran P55, Swart KMA192, Tardif JC9,86, Taylor KD14, Teumer A193, Thompson DJ80, Thorleifsson G189, Thorsteinsdottir U189,190, Thuesen BH121, Tönjes A194, Torres M195, Tsafantakis E196, Tuomilehto J122,197,198,199, Uitterlinden AG20,21, Uusitupa M200, van Duijn CM20, Vanhala M201,202, Varma R195, Vermeulen SH203, Vestergaard H50,204, Vitart V108, Vogt TF205, Vuckovic D99,100, Wagenknecht LE206, Walker M207, Wallentin L208, Wang F111, Wang CA165,166, Wang S152, Wareham NJ31, Warren HR16,57, Waterworth DM209, Wessel J210, White HD211, Willer CJ123,124,212, Wilson JG213, Wood AR180, Wu Y174, Yaghootkar H180, Yao J14, Yerges-Armstrong LM164,214, Young R55,215, Zeggini E72, Zhan X216, Zhang W60,61, Zhao JH31, Zhao W181, Zheng H111, Zhou W123,124, Zillikens MC20,21; CHD Exome+ Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetic Consortium; GoT2D Genes Consortium; InterAct; ReproGen Consortium; T2D-Genes Consortium; MAGIC Investigators, Rivadeneira F20,21, Borecki IB28, Pospisilik JA15, Deloukas P16,217, Frayling TM180, Lettre G9,86, Mohlke KL174, Rotter JI14, Kutalik Z43,218, Hirschhorn JN11,13,219, Cupples LA27,152, Loos RJF7,8,220, North KE221, Lindgren CM222,223.

Author information

1
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
2
Weis Center for Research, Geisinger Health System, Danville, PA, USA.
3
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
4
Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus.
5
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
6
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
7
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada.
10
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
11
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
12
Department of Genetics, Harvard Medical School, Boston, MA, USA.
13
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
14
Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
15
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
16
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
17
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
18
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
19
McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, USA.
20
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
21
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
22
Estonian Genome Center, University of Tartu, Tartu, Estonia.
23
Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
24
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
25
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
26
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
27
NHLBI Framingham Heart Study, Framingham, MA, USA.
28
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
29
Department of Medicine, Harvard University Medical School, Boston, MA, USA.
30
Massachusetts General Hospital, Boston, MA, USA.
31
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
32
Department of Vascular Medicine, AMC, Amsterdam, The Netherlands.
33
Department of Haematology, University of Cambridge, Cambridge, UK.
34
School of Public Health, University of Michigan, Ann Arbor, MI, USA.
35
School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada.
36
Department of Family Medicine & Public Health, University of California, San Diego, La Jolla, CA, USA.
37
INSERM U1167, Lille, France.
38
Institut Pasteur de Lille, U1167, Lille, France.
39
U1167-RID-AGE, Universite de Lille - Risk factors and molecular determinants of aging-related diseases, Lille, France.
40
INSERM U1018, Centre de recherche en Épidemiologie et Sante des Populations (CESP), Villejuif, France.
41
Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
42
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
43
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
44
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
45
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
46
Department of Medicine, University of Leipzig, Leipzig, Germany.
47
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
48
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
49
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
50
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
51
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
52
Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
53
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
54
Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
55
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
56
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
57
NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
58
Research Centre on Public Health, University of Milano-Bicocca, Monza, Italy.
59
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
60
Department of Cardiology, London North West Healthcare NHS Trust, Ealing Hospital, Middlesex, UK.
61
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
62
Imperial College Healthcare NHS Trust, London, UK.
63
MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
64
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
65
Division of Preventive Medicine, Brigham and Women's and Harvard Medical School, Boston, MA, USA.
66
Harvard Medical School, Boston, MA, USA.
67
Medical department, Lillebaelt Hospital, Vejle, Denmark.
68
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
69
Department of Biostatistics, University of Liverpool, Liverpool, UK.
70
Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia.
71
Department of Biomedical Infomatics and Medical Education, University of Washington, Seattle, WA, USA.
72
Wellcome Trust Sanger Institute, Hinxton, UK.
73
British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK.
74
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
75
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
76
Faculty of Pharmacy, Universite de Montreal, Montreal, Quebec, Canada.
77
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
78
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
79
Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
80
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
81
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
82
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
83
Institute of Cardiovascular Science, University College London, London, UK.
84
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
85
Department of Life Sciences, Brunel University London, Uxbridge, UK.
86
Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada.
87
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
88
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
89
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
90
CNR Institute of Clinical Physiology, Pisa, Italy.
91
Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy.
92
Toulouse University School of Medicine, Toulouse, France.
93
Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
94
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmo, Sweden.
95
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
96
Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.
97
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
98
Ilaria Gandin, Research Unit, AREA Science Park, Trieste, Italy.
99
Department of Medical Sciences, University of Trieste, Trieste, Italy.
100
Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.
101
Geriatrics, Department of Public Health, Uppsala University, Uppsala, Sweden.
102
German Center for Diabetes Research, München-Neuherberg, Germany.
103
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
104
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
105
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
106
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle WA, USA.
107
University of Exeter Medical School, University of Exeter, Exeter, UK.
108
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
109
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
110
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
111
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
112
Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
113
School of Medicine, National Defense Medical Center, Taipei, Taiwan.
114
HUNT Research Center, Department of Public Health, Norwegian University of Science and Technology, Levanger, Norway.
115
Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
116
Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.
117
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
118
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
119
Faculty of Medicine, Aalborg University, Aalborg, Denmark.
120
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
121
Research Center for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark.
122
National Institute for Health and Welfare, Helsinki, Finland.
123
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
124
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
125
Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
126
Centre for Brain Research, Indian Institute of Science, Bangalore, India.
127
Echinos Medical Centre, Echinos, Greece.
128
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
129
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
130
UKCRC Centre of Excellence for Public Health Research, Queens University Belfast, Belfast, UK.
131
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
132
National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK.
133
University Medical Centre Mannheim, 5th Medical Department, University of Heidelberg, Mannheim, Germany.
134
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
135
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Finland.
136
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
137
Verge Genomics, San Fransico, CA, USA.
138
Division of Biomedical and Personalized Medicine, Department of Medicine, University of Colorado-Denver, Aurora, CO, USA.
139
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
140
Department of Health Services, University of Washington, Seattle, WA, USA.
141
Department of Anthropology, Sociology, and History, University of San Carlos, Cebu City, Philippines.
142
USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines.
143
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
144
Department of Social Work, Tunghai University, Taichung, Taiwan.
145
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
146
Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
147
Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
148
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.
149
Uppsala University, Uppsala, Sweden.
150
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.
151
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
152
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
153
Department of Public Health Sciences, Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
154
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
155
Department of Cardiovascular Sciences, Univeristy of Leicester, Glenfield Hospital, Leicester, UK.
156
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
157
Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
158
Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
159
Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France.
160
Department of Public Health, University Hospital of Strasbourg, Strasbourg, France.
161
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
162
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universitat, Munich, Germany.
163
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
164
Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
165
Division of Obstetric and Gynaecology, School of Medicine, The University of Western Australia, Perth, Western Australia, Australia.
166
School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, New South Wales, Australia.
167
Institute for Molecular Medicine (FIMM) and Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
168
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
169
School of Medicine, University of Split, Split, Croatia.
170
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
171
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
172
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
173
Centre for Non-Communicable Diseases, Karachi, Pakistan.
174
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
175
Genetics and Pharmacogenomics, Merck & Co., Inc., Boston, MA, USA.
176
Department of Epidemiology, University of Washington, Seattle, WA, USA.
177
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
178
Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
179
Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
180
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
181
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
182
Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN, USA.
183
Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, Singapore.
184
Genetics, Target Sciences, GlaxoSmithKline, Research Triangle Park, NC, USA.
185
OmicSoft a QIAGEN Company, Cary, NC, USA.
186
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
187
Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
188
Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
189
deCODE Genetics/Amgen Inc., Reykjavik, Iceland.
190
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
191
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany.
192
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
193
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
194
Center for Pediatric Research, Department for Women's and Child Health, University of Leipzig, Leipzig, Germany.
195
USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
196
Anogia Medical Centre, Anogia, Greece.
197
Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
198
Dasman Diabetes Institute, Dasman, Kuwait.
199
Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
200
Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
201
Central Finland Central Hospital, Jyvaskyla, Finland.
202
University of Eastern Finland, Kuopio, Finland.
203
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
204
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
205
Cardiometabolic Disease, Merck & Co., Inc., Kenilworth, NJ, USA.
206
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
207
Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, UK.
208
Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
209
Genetics, Target Sciences, GlaxoSmithKline, Collegeville, PA, USA.
210
Departments of Epidemiology & Medicine, Diabetes Translational Research Center, Fairbanks School of Public Health & School of Medicine, Indiana University, Indiana, IN, USA.
211
Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland, New Zealand.
212
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
213
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
214
GlaxoSmithKline, King of Prussia, PA, USA.
215
University of Glasgow, Glasgow, UK.
216
Department of Clinical Sciences, Quantitative Biomedical Research Center, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
217
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
218
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
219
Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, USA.
220
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
221
Department of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. kari_north@unc.edu.
222
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. celi@well.ox.ac.uk.
223
Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford, UK. celi@well.ox.ac.uk.

Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

PMID:
30778226
DOI:
10.1038/s41588-018-0334-2

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