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Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.

Zheng HF1,2, Forgetta V1,2, Hsu YH3,4,5, Estrada K4,5,6,7, Rosello-Diez A8, Leo PJ9, Dahia CL10,11, Park-Min KH12, Tobias JH13,14, Kooperberg C15, Kleinman A16, Styrkarsdottir U17, Liu CT18, Uggla C19, Evans DS20, Nielson CM21,22, Walter K23, Pettersson-Kymmer U24,25, McCarthy S23, Eriksson J19,26, Kwan T27, Jhamai M6, Trajanoska K6,28, Memari Y23, Min J14, Huang J23, Danecek P23, Wilmot B29,30, Li R1,2, Chou WC3,4, Mokry LE2, Moayyeri A31,32, Claussnitzer M3,4,5,33, Cheng CH3, Cheung W27,34, Medina-Gómez C6,28,35, Ge B27, Chen SH27, Choi K36, Oei L6,28,35, Fraser J37, Kraaij R6,28,35, Hibbs MA36,38, Gregson CL39, Paquette D37, Hofman A28,35, Wibom C40, Tranah GJ21,22, Marshall M9, Gardiner BB9, Cremin K9, Auer P41, Hsu L15, Ring S42, Tung JY16, Thorleifsson G43, Enneman AW6, van Schoor NM44, de Groot LC45, van der Velde N6,46, Melin B40, Kemp JP9,14, Christiansen C47, Sayers A39, Zhou Y18, Calderari S48,49, van Rooij J6,35, Carlson C15, Peters U15, Berlivet S37, Dostie J37, Uitterlinden AG6,28,35, Williams SR50, Farber C50, Grinberg D51,52,53, LaCroix AZ54, Haessler J15, Chasman DI4,55, Giulianini F55, Rose LM55, Ridker PM4,55, Eisman JA56,57,58, Nguyen TV56,58, Center JR56,58, Nogues X59,60,61, Garcia-Giralt N59,60, Launer LL62, Gudnason V63,64, Mellström D19, Vandenput L19, Amin N65, van Duijn CM65, Karlsson MK66, Ljunggren Ö67, Svensson O68, Hallmans G25, Rousseau F69,70, Giroux S70, Bussière J70, Arp PP6, Koromani F6,28, Prince RL71,72, Lewis JR71,72, Langdahl BL73, Hermann AP74, Jensen JE75, Kaptoge S31, Khaw KT76, Reeve J77,78, Formosa MM79, Xuereb-Anastasi A79, Åkesson K66,80, McGuigan FE80, Garg G80, Olmos JM81,82, Zarrabeitia MT83, Riancho JA81,82, Ralston SH84, Alonso N84, Jiang X85, Goltzman D86, Pastinen T27,34, Grundberg E27,34, Gauguier D48,49, Orwoll ES22,87, Karasik D3,88, Davey-Smith G14; AOGC Consortium, Smith AV63,64, Siggeirsdottir K63, Harris TB89, Zillikens MC6, van Meurs JB6,28, Thorsteinsdottir U17,64, Maurano MT90, Timpson NJ14, Soranzo N23, Durbin R23, Wilson SG32,71,91, Ntzani EE92,93, Brown MA9, Stefansson K64,94, Hinds DA16, Spector T32, Cupples LA18,95, Ohlsson C19, Greenwood CM2,34,96,97; UK10K Consortium, Jackson RD98, Rowe DW85, Loomis CA99, Evans DM9,14, Ackert-Bicknell CL36, Joyner AL8, Duncan EL9,100, Kiel DP3,4,5,33, Rivadeneira F6,28,35, Richards JB1,2,32.

Author information

1
Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.
2
Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.
3
Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.
4
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA.
6
Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
7
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
8
Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA.
9
The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
10
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.
11
Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA.
12
Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA.
13
School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK.
14
MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
15
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
16
Department of Research, 23andMe, Mountain View, California 94041, USA.
17
Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland.
18
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
19
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
20
California Pacific Medical Center Research Institute, San Francisco, California 94158, USA.
21
Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.
22
Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA.
23
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
24
Departments of Pharmacology and Clinical Neurosciences, Umeå University, Umeå S-901 87, Sweden.
25
Department of Public Health and Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden.
26
Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
27
McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.
28
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
29
Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
30
Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA.
31
Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK.
32
Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
33
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
34
Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.
35
Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
36
Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA.
37
Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada.
38
Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA.
39
Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK.
40
Department of Radiation Sciences, Umeå University, Umeå S-901 87, Sweden.
41
School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA.
42
School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
43
Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland.
44
Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.
45
Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands.
46
Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands.
47
Nordic Bioscience, Herlev 2730, Denmark.
48
Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France.
49
Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France.
50
Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
51
Department of Genetics, University of Barcelona, Barcelona 08028, Spain.
52
U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain.
53
Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.
54
Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA.
55
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
56
Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia.
57
School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia.
58
St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia.
59
Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.
60
Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain.
61
Department of Internal Medicine, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona 08193, Spain.
62
Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
63
Icelandic Heart Association, Kopavogur IS-201, Iceland.
64
Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.
65
Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands.
66
Department of Orthopaedics, Skåne University Hospital Malmö 205 02, Sweden.
67
Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden.
68
Department of Surgical and Perioperative Sciences, Umeå Unviersity, Umeå 901 85, Sweden.
69
Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City G1V 0A6, Canada.
70
Axe Santé des Populations et Pratiques Optimales en Santé, Centre de recherche du CHU de Québec, Québec City G1V 4G2, Canada.
71
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia.
72
Department of Medicine, University of Western Australia, Perth 6009, Australia.
73
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark.
74
Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark.
75
Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark.
76
Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK.
77
Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
78
Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
79
Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta.
80
Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University, 205 02, Sweden.
81
Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain.
82
Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain.
83
Department of Legal Medicine, University of Cantabria, Santander 39011, Spain.
84
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
85
Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
86
Department of Medicine and Physiology, McGill University, Montréal H4A 3J1, Canada.
87
Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.
88
Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel.
89
Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
90
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
91
School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia.
92
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
93
Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA.
94
deCODE Genetics, Reykjavik IS-101, Iceland.
95
Framingham Heart Study, Framingham, Massachusetts 01702, USA.
96
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal H3A 1A2, Canada.
97
Department of Oncology, Gerald Bronfman Centre, McGill University, Montréal H2W 1S6, Canada.
98
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA.
99
The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
100
Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.

Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

PMID:
26367794
PMCID:
PMC4755714
DOI:
10.1038/nature14878
[Indexed for MEDLINE]
Free PMC Article

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