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

doi:10.1016/j.ajhg.2017.04.014

. 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

Ioanna Tachmazidou¹, Dániel Süveges¹, Josine L Min², Graham R S Ritchie³, Julia Steinberg¹, Klaudia Walter¹, Valentina Iotchkova⁴, Jeremy Schwartzentruber¹, Jie Huang⁵, Yasin Memari¹, Shane McCarthy¹, Andrew A Crawford⁶, Cristina Bombieri⁷, Massimiliano Cocca⁸, Aliki-Eleni Farmaki⁹, Tom R Gaunt², Pekka Jousilahti¹⁰, Marjolein N Kooijman¹¹, Benjamin Lehne¹², Giovanni Malerba⁷, Satu Männistö¹⁰, Angela Matchan¹, Carolina Medina-Gomez¹³, Sarah J Metrustry¹⁴, Abhishek Nag¹⁴, Ioanna Ntalla¹⁵, Lavinia Paternoster², Nigel W Rayner¹⁶, Cinzia Sala¹⁷, William R Scott¹⁸, Hashem A Shihab², Lorraine Southam¹⁹, Beate St Pourcain²⁰, Michela Traglia¹⁷, Katerina Trajanoska¹³, Gialuigi Zaza²¹, Weihua Zhang¹⁸, María S Artigas²², Narinder Bansal²³, Marianne Benn²⁴, Zhongsheng Chen²⁵, Petr Danecek²⁴, Wei-Yu Lin²³, Adam Locke²⁶, Jian'an Luan²⁷, Alisa K Manning²⁸, Antonella Mulas²⁹, Carlo Sidore³⁰, Anne Tybjaerg-Hansen²⁴, Anette Varbo²⁴, Magdalena Zoledziewska³⁰, Chris Finan³¹, Konstantinos Hatzikotoulas¹, Audrey E Hendricks³², John P Kemp³³, Alireza Moayyeri³⁴, Kalliope Panoutsopoulou¹, Michal Szpak¹, Scott G Wilson³⁵, Michael Boehnke²⁵, Francesco Cucca²⁹, Emanuele Di Angelantonio³⁶, Claudia Langenberg²⁷, Cecilia Lindgren³⁷, Mark I McCarthy³⁸, Andrew P Morris³⁹, Børge G Nordestgaard²⁴, Robert A Scott²⁷, Martin D Tobin⁴⁰, Nicholas J Wareham²⁷; SpiroMeta Consortium; GoT2D Consortium; Paul Burton⁴¹, John C Chambers⁴², George Davey Smith², George Dedoussis⁹, Janine F Felix¹¹, Oscar H Franco⁴³, Giovanni Gambaro⁴⁴, Paolo Gasparini⁴⁵, Christopher J Hammond¹⁴, Albert Hofman⁴³, Vincent W V Jaddoe¹¹, Marcus Kleber⁴⁶, Jaspal S Kooner⁴⁷, Markus Perola⁴⁸, Caroline Relton², Susan M Ring², Fernando Rivadeneira¹³, Veikko Salomaa¹⁰, Timothy D Spector¹⁴, Oliver Stegle⁴⁹, Daniela Toniolo¹⁷, André G Uitterlinden¹³; arcOGEN Consortium; Understanding Society Scientific Group; UK10K Consortium; Inês Barroso⁵⁰, Celia M T Greenwood⁵¹, John R B Perry⁵², Brian R Walker⁵³, Adam S Butterworth³⁶, Yali Xue¹, Richard Durbin¹, Kerrin S Small¹⁴, Nicole Soranzo⁵⁴, Nicholas J Timpson², Eleftheria Zeggini⁵⁵

Affiliations

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.

PMID: 28552196
PMCID: PMC5473732
DOI: 10.1016/j.ajhg.2017.04.014

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

Ioanna Tachmazidou et al. Am J Hum Genet. 2017.

. 2017 Jun 1;100(6):865-884.

doi: 10.1016/j.ajhg.2017.04.014. Epub 2017 May 25.

Authors

Affiliations

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.

PMID: 28552196
PMCID: PMC5473732
DOI: 10.1016/j.ajhg.2017.04.014

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.

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Figures

**Figure 1**
Heatmap of Pairwise Genetic Correlation Estimates between Anthropometric Traits Correlation estimates with their 95% confidence intervals and 5% FDR q values across all 66 possible pairs are given in Table S6. Abbreviations are as follows: BMI, body mass index; WHR, waist to hip ratio; WaistBMIadj, waist circumference adjusted for BMI; HipBMIadj, hip circumference adjusted for BMI; WHRBMIadj, waist to hip ratio adjusted for BMI; TFM, total fat mass; TLM, total lean mass; TRFM, trunk fat mass.

**Figure 2**
Enrichment of Discovery Meta-analysis Results in Mendelian Height-, Monogenic Obesity-, Syndromic Obesity-, and Mendelian Lipodystrophy-Associated Genes We used independent variants (r² < 0.2) with MAF ≥ 0.1% (left) and after excluding previously reported loci (±500 kb) (right). Shown are Mendelian height (A and B), monogenic obesity (C and D), syndromic obesity (E and F), and Mendelian lipodystrophy (G and H). Enrichment of signal is observed if the p value (one-sided) from the binomial test of the observed versus the expected number of variants with p ≤ 10⁻⁵ in Mendelian-associated genes (as calculated by GREAT and denoted by the red dot) is less than 0.05/4.482 (5% significance level Bonferroni corrected for the effective number of independent traits; horizontal red line). Observed and expected counts, Bonferroni corrected p values, and FDR q values are given in Table S24. Abbreviations are as follows: BMI, body mass index; WHR, waist to hip ratio; WaistBMIadj, waist circumference adjusted for BMI; HipBMIadj, hip circumference adjusted for BMI; WHRBMIadj, waist to hip ratio adjusted for BMI; TFM, total fat mass; TLM, total lean mass; TRFM, trunk fat mass.

**Figure 3**
Combined Information from Fine-Mapping Methods, Functional Prediction Scores, and eQTL Analysis to Assess the Overall Evidence Supporting Functional and Causal Interpretation at Fine-Mapped Regions of Newly Identified Variants Example of fine-mapping and annotation at the *ADAMTS17* (left) and *SSC5D* (right) loci for association with height. LocusZoom regional association plot shown in (A) and posterior probability (PP) statistics shown in (B) are from the fine-mapping methods CAVIARBF and PRFScore (only variants with PP > 0.1 in either methods are shown); genome-wide annotation of variants (GWAVA) scores; genomic evolutionary rate profiling (GERP) scores; average GERP (in a 100 bp window around each variant) scores; whether the variant is an eQTL signal; number of cell lines in which the variant overlaps with a DNase footprints (peak calls from ENCODE); number of overlapping transcriptional factor binding sites based on ENCODE and JASPAR ChIP-seq; number of cell lines in which the queried locus overlaps with a DNase hypersensitivity site (ENCODE data, peaks from Ensembl); and Variant Effect Predictor (VEP) genic annotation. Circle sizes and colors for all scores are scaled with respect to score type and numbers are plotted below each circle. Probabilities of causality from CAVIARBF and PRFScore are colored in shades of purple. GWAVA scores range between [0,1] and scores greater than 0.5 indicate functionality (colored in white for scores < 0.5 and in shades of orchid for scores > 0.5). GERP scores range between [−12.3,6.17] with scores above zero indicating constraint (colored in white for scores < 0 and in shades of orchid for scores > 0).

**Figure 4**
Power to Detect Association in the Discovery Stage, Stage 1 Effect sizes and 95% confidence intervals (absolute value of beta, expressed in standard deviation units) as a function of minor allele frequencies (MAF), based on stage 1 of this study. Newly reported variants are denoted in diamonds, and previously reported variants that reach genome-wide significance (p ≤ 5 × 10⁻⁸, two-sided) in the discovery stage are denoted in circles. The curves indicate 80% power at the genome-wide significance threshold of p ≤ 5 × 10⁻⁸, for five representative sample sizes of the discovery stage: (1) height, BMI, weight; (2) TFM, TLM; (3) TRFM; (4) waist circumference, waist circumference adjusted for BMI; (5) hip circumference, waist to hip ratio, hip circumference adjusted for BMI, waist to hip ratio adjusted for BMI. The sample size for height (blue line) had 80% power to detect associations down to 0.1% MAF for betas ≥ 0.19 standard deviations (0.36 and 0.23 for TFM [orange] and waist to hip ratio [purple], respectively; not plotted). Further power calculations for different sample sizes are given in Figure S32. Abbreviations are as follows: BMI, body mass index; WHR, waist to hip ratio; WaistBMIadj, waist circumference adjusted for BMI; HipBMIadj, hip circumference adjusted for BMI; WHRBMIadj, waist to hip ratio adjusted for BMI; TFM, total fat mass; TLM, total lean mass; TRFM, trunk fat mass.

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References

1. Haslam D.W., James W.P. Obesity. Lancet. 2005;366:1197–1209. - PubMed
1. Barness L.A., Opitz J.M., Gilbert-Barness E. Obesity: genetic, molecular, and environmental aspects. Am. J. Med. Genet. A. 2007;143A:3016–3034. - PubMed
1. Berrington de Gonzalez A., Hartge P., Cerhan J.R., Flint A.J., Hannan L., MacInnis R.J., Moore S.C., Tobias G.S., Anton-Culver H., Freeman L.B. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211–2219. - PMC - PubMed
1. Locke A.E., Kahali B., Berndt S.I., Justice A.E., Pers T.H., Day F.R., Powell C., Vedantam S., Buchkovich M.L., Yang J., LifeLines Cohort Study. ADIPOGen Consortium. AGEN-BMI Working Group. CARDIOGRAMplusC4D Consortium. CKDGen Consortium. GLGC. ICBP. MAGIC Investigators. MuTHER Consortium. MIGen Consortium. PAGE Consortium. ReproGen Consortium. GENIE Consortium. International Endogene Consortium Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206. - PMC - PubMed
1. Shungin D., Winkler T.W., Croteau-Chonka D.C., Ferreira T., Locke A.E., Mägi R., Strawbridge R.J., Pers T.H., Fischer K., Justice A.E., ADIPOGen Consortium. CARDIOGRAMplusC4D Consortium. CKDGen Consortium. GEFOS Consortium. GENIE Consortium. GLGC. ICBP. International Endogene Consortium. LifeLines Cohort Study. MAGIC Investigators. MuTHER Consortium. PAGE Consortium. ReproGen Consortium New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–196. - PMC - PubMed

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[1] Haslam D.W., James W.P. Obesity. Lancet. 2005;366:1197–1209. - PubMed

[2] Haslam D.W., James W.P. Obesity. Lancet. 2005;366:1197–1209. - PubMed

[3] Barness L.A., Opitz J.M., Gilbert-Barness E. Obesity: genetic, molecular, and environmental aspects. Am. J. Med. Genet. A. 2007;143A:3016–3034. - PubMed

[4] Barness L.A., Opitz J.M., Gilbert-Barness E. Obesity: genetic, molecular, and environmental aspects. Am. J. Med. Genet. A. 2007;143A:3016–3034. - PubMed

[5] Berrington de Gonzalez A., Hartge P., Cerhan J.R., Flint A.J., Hannan L., MacInnis R.J., Moore S.C., Tobias G.S., Anton-Culver H., Freeman L.B. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211–2219. - PMC - PubMed

[6] Berrington de Gonzalez A., Hartge P., Cerhan J.R., Flint A.J., Hannan L., MacInnis R.J., Moore S.C., Tobias G.S., Anton-Culver H., Freeman L.B. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211–2219. - PMC - PubMed

[7] Locke A.E., Kahali B., Berndt S.I., Justice A.E., Pers T.H., Day F.R., Powell C., Vedantam S., Buchkovich M.L., Yang J., LifeLines Cohort Study. ADIPOGen Consortium. AGEN-BMI Working Group. CARDIOGRAMplusC4D Consortium. CKDGen Consortium. GLGC. ICBP. MAGIC Investigators. MuTHER Consortium. MIGen Consortium. PAGE Consortium. ReproGen Consortium. GENIE Consortium. International Endogene Consortium Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206. - PMC - PubMed

[8] Locke A.E., Kahali B., Berndt S.I., Justice A.E., Pers T.H., Day F.R., Powell C., Vedantam S., Buchkovich M.L., Yang J., LifeLines Cohort Study. ADIPOGen Consortium. AGEN-BMI Working Group. CARDIOGRAMplusC4D Consortium. CKDGen Consortium. GLGC. ICBP. MAGIC Investigators. MuTHER Consortium. MIGen Consortium. PAGE Consortium. ReproGen Consortium. GENIE Consortium. International Endogene Consortium Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206. - PMC - PubMed

[9] Shungin D., Winkler T.W., Croteau-Chonka D.C., Ferreira T., Locke A.E., Mägi R., Strawbridge R.J., Pers T.H., Fischer K., Justice A.E., ADIPOGen Consortium. CARDIOGRAMplusC4D Consortium. CKDGen Consortium. GEFOS Consortium. GENIE Consortium. GLGC. ICBP. International Endogene Consortium. LifeLines Cohort Study. MAGIC Investigators. MuTHER Consortium. PAGE Consortium. ReproGen Consortium New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–196. - PMC - PubMed

[10] Shungin D., Winkler T.W., Croteau-Chonka D.C., Ferreira T., Locke A.E., Mägi R., Strawbridge R.J., Pers T.H., Fischer K., Justice A.E., ADIPOGen Consortium. CARDIOGRAMplusC4D Consortium. CKDGen Consortium. GEFOS Consortium. GENIE Consortium. GLGC. ICBP. International Endogene Consortium. LifeLines Cohort Study. MAGIC Investigators. MuTHER Consortium. PAGE Consortium. ReproGen Consortium New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–196. - PMC - PubMed

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

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

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