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Am J Hum Genet. 2017 Jun 1;100(6):865-884. doi: 10.1016/j.ajhg.2017.04.014. Epub 2017 May 25.

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Author information

1
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
2
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
3
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; Usher Institute of Population Health Sciences & Informatics, University of Edinburgh, Edinburgh EH16 4UX, UK; MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4UX, UK.
4
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
5
Boston VA Research Institute, Boston, MA 02130, USA.
6
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK; BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
7
Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona 37134, Italy.
8
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy.
9
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens 17671, Greece.
10
Department of Health, National Institute for Health and Welfare, Helsinki 00271, Finland.
11
The Generation R Study Group, Erasmus Medical Center, University Medical Center, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam 3000 CA, the Netherlands; Department of Pediatrics, Erasmus Medical Center, University Medical Center, Rotterdam 3000 CA, the Netherlands.
12
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK.
13
Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam 3000 CA, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, University Medical Center, Rotterdam 3000 CA, the Netherlands.
14
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
15
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
16
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
17
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
18
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital NHS Trust, Middlesex UB1 3EU, UK.
19
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
20
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK; Max Planck Institute for Psycholinguistics, Nijmegen 6500, the Netherlands.
21
Renal Unit, Department of Medicine, Verona University Hospital, Verona 37126, Italy.
22
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
23
Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
24
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark.
25
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
26
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO 63108, USA.
27
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
28
Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Harvard University Medical School, Boston, MA 02115, USA.
29
Istituto di Ricerca Genetica e Biomedica (IRGB-CNR), Cagliari 09100, Italy; Università degli Studi di Sassari, Sassari 07100, Italy.
30
Istituto di Ricerca Genetica e Biomedica (IRGB-CNR), Cagliari 09100, Italy.
31
Institute of Cardiovascular Science, Faculty of Population Health, University College London, London WC1E 6BT, UK.
32
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO 80204, USA.
33
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4072, Australia.
34
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK; Institute of Health Informatics, University College London, London NW1 2DA, UK.
35
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK; School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA 6009, Australia; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia.
36
Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge CB1 8RN, UK.
37
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford OX3 7BN, UK.
38
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
39
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK; Estonian Genome Center, University of Tartu, Tartu, Tartumaa 51010, Estonia.
40
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
41
D2K Research Group, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
42
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital NHS Trust, Middlesex UB1 3EU, UK; Imperial College Healthcare NHS Trust, London W2 1NY, UK.
43
Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam 3000 CA, the Netherlands.
44
Division of Nephrology and Dialysis, Columbus-Gemelli University Hospital, Catholic University, Rome 00168, Italy.
45
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34100, Italy; Medical Genetics, Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste 34100, Italy.
46
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
47
Department of Cardiology, Ealing Hospital NHS Trust, Middlesex UB1 3EU, UK; Imperial College Healthcare NHS Trust, London W2 1NY, UK; National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
48
Department of Health, National Institute for Health and Welfare, Helsinki 00271, Finland; Estonian Genome Center, University of Tartu, Tartu, Tartumaa 51010, Estonia; Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki 00290, Finland.
49
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
50
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
51
Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, QC H3A 1A2, Canada; Department of Oncology, McGill University, Montréal, QC H2W 1S6, Canada.
52
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
53
BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
54
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge CB1 8RN, UK; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
55
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. Electronic address: eleftheria@sanger.ac.uk.

Abstract

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

KEYWORDS:

DXA traits; UK Biobank; UK10K; anthropometry; genetic association study; imputation; next-generation whole-genome sequencing

PMID:
28552196
PMCID:
PMC5473732
DOI:
10.1016/j.ajhg.2017.04.014
[Indexed for MEDLINE]
Free PMC Article

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