Whole‐genome sequencing identifies <em>EN1</em> as a determinant of bone density and fracture

Zheng, Hou-Feng; Forgetta, Vincenzo; Hsu, Yi-Hsiang; Estrada, Karol; Rosello-Diez, Alberto; Leo, Paul J.; Dahia, Chitra L.; Park-Min, Kyung Hyun; Tobias, Jonathan H; Kooperberg, Charles; Kleinman, Aaron; Styrkarsdottir, Unnur; Liu, Ching-Ti; Uggla, Charlotta; Evans, Daniel S.; Nielson, Carrie M.; Walter, Klaudia; Pettersson-Kymmer, Ulrika; McCarthy, Shane; Eriksson, Joel; Kwan, Tony; Jhamai, Mila; Trajanoska, Katerina; Memari, Yasin; Min, Josine; Huang, Jie; Danecek, Petr; Wilmot, Beth; Li, Rui; Chou, Wen-Chi; Mokry, Lauren E.; Moayyeri, Alireza; Claussnitzer, Melina; Cheng, Chia-Ho; Cheung, Warren; Medina-Gómez, Carolina; Ge, Bing; Chen, Shu-Huang; Choi, Kwangbom; Oei, Ling; Fraser, James; Kraaij, Robert; Hibbs, Matthew A.; Gregson, Celia L.; Paquette, Denis; Hofman, Albert; Wibom, Carl; Tranah, Gregory J.; Marshall, Mhairi; Gardiner, Brooke B.; Cremin, Katie; Auer, Paul; Hsu, Li; Ring, Sue; Tung, Joyce Y.; Thorleifsson, Gudmar; Enneman, Anke W.; van Schoor, Natasja M.; M., de Groot Lisette C. P. G.; Nathalie, van der Velde; Melin, Beatrice; Kemp, John P.; Christiansen, Claus; Sayers, Adrian; Zhou, Yanhua; Calderari, Sophie; van Rooij, Jeroen; Carlson, Chris; Peters, Ulrike; Berlivet, Soizik; Dostie, Josée; Uitterlinden, Andre G.; Williams, Stephen R; Farber, Charles; Grinberg, Daniel; LaCroix, Andrea Z.; Haessler, Jeff; Chasman, Daniel I.; Giulianini, Franco; Rose, Lynda M.; Ridker, Paul M.; Eisman, John A.; Nguyen, Tuan V; Center, Jacqueline R; Nogues, Xavier; Garcia-Giralt, Natalia; Launer, Lenore L.; Gudnason, Vilmunder; Mellström, Dan; Vandenput, Liesbeth; Amin, Najaf; M., van Duijn Cornelia; Karlsson, Magnus K; Ljunggren, Östen; Svensson, Olle; Hallmans, Göran; Rousseau, François; Giroux, Sylvie; Bussière, Johanne; Arp, Pascal P.; Koromani, Fjorda; Prince, Richard L.; Lewis, Joshua R; Langdahl, Bente L.; Hermann, A Pernille; Jensen, Jens-Erik B.; Kaptoge, Stephen; Khaw, Kay-Tee; Reeve, Jonathan; Formosa, Melissa M.; Xuereb-Anastasi, Angela; Åkesson, Kristina; McGuigan, Fiona E; Garg, Gaurav; Olmos, Jose M.; Zarrabeitia, Maria T.; Riancho, Jose A.; Ralston, Stuart H; Alonso, Nerea; Jiang, Xi; Goltzman, David; Pastinen, Tomi; Grundberg, Elin; Gauguier, Dominique; Orwoll, Eric S.; Karasik, David; Davey-Smith, George; Smith, Albert V.; Siggeirsdottir, Kristin; Harris, Tamara B.; Zillikens, M Carola; J., van Meurs Joyce B.; Thorsteinsdottir, Unnur; Maurano, Matthew T.; Timpson, Nicholas J.; Soranzo, Nicole; Durbin, Richard; Wilson, Scott G.; Ntzani, Evangelia E; Brown, Matthew A.; Stefansson, Kari; Hinds, David A.; Spector, Tim; Cupples, L. Adrienne; Ohlsson, Claes; Greenwood, Celia M. T.; Jackson, Rebecca D.; Rowe, David W; Loomis, Cynthia A.; Evans, David M.; Ackert-Bicknell, Cheryl L.; Joyner, Alexandra L.; Duncan, Emma L.; Kiel, Douglas P.; Rivadeneira, Fernando; Richards, J. Brent

Affiliations

¹Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada

²Department of Medicine, Lady Davis Institute forMedical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada

³Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA

⁴Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

⁵Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA

⁶Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands

⁷Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

⁸Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA

⁹The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia

¹⁰Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA

¹¹Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA

¹²Rheumatology Divison, Hospital for Special Surgery, New York 10021, USA

¹³School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK

¹⁴MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK

¹⁵Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA

¹⁶Department of Research, 23andMe, Mountain View, California 94041, USA

¹⁷Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland

¹⁸Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA

¹⁹Centre 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

²⁰California Pacific Medical Center Research Institute, San Francisco, California 94158, USA

²¹Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA

²²Bone & Mineral Unit, Oregon Health & Science University, Portland, Oregon 97239, USA

²³Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK

²⁴Departments of Pharmacology and Clinical Neurosciences, Umeå University, Umeå S-901 87, Sweden

²⁵Department of Public Health and Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden

²⁶Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden

²⁷McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada

²⁸Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands

²⁹Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239, USA

³⁰Department of Medical and Clinical Informatics, Oregon Health & Science University, Portland, Oregon 97239, USA

³¹Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK

³²Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK

³³Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

³⁴Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada

³⁵Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands

³⁶Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA

³⁷Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada

³⁸Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA

³⁹Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK

⁴⁰Department of Radiation Sciences, Umeå University, Umeå S-901 87, Sweden

⁴¹School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA

⁴²School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK

⁴³Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland

⁴⁴Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands

⁴⁵Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands

⁴⁶Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands

⁴⁷Nordic Bioscience, Herlev 2730, Denmark

⁴⁸Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France

⁴⁹Institute of Cardiometabolism and Nutrition, University Pierre & Marie Curie, Paris 75013, France

⁵⁰Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA

⁵¹Department of Genetics, University of Barcelona, Barcelona 08028, Spain

⁵²U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain

⁵³Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain

⁵⁴Women’s Health Center of Excellence Family Medicine and Public Health, University of California – San Diego, San Diego, California 92093, USA

⁵⁵Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA

⁵⁶Osteoporosis & Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia

⁵⁷School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia

⁵⁸St. Vincent’s Hospital & Clinical School, NSW University, Sydney 2010, Australia

⁵⁹Musculoskeletal Research Group, Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona 08003, Spain

⁶⁰Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain

⁶¹Department of Internal Medicine, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona 08193, Spain

⁶²Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA

⁶³Icelandic Heart Association, Kopavogur IS-201, Iceland

⁶⁴Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland

⁶⁵Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands

⁶⁶Department of Orthopaedics, Skåne University Hospital Malmö 205 02, Sweden

⁶⁷Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden

⁶⁸Department of Surgical and Perioperative Sciences, Umeå Unviersity, Umeå 901 85, Sweden

⁶⁹Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City G1V 0A6, Canada. 70

⁷⁰Axe Santé des Populations et Pratiques Optimales en Santé, Centre de recherche du CHU de Québec, Québec City G1V 4G2, Canada

⁷¹Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia

⁷²Department of Medicine, University of Western Australia, Perth 6009, Australia

⁷³Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark

⁷⁴Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark

⁷⁵Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark

⁷⁶Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK

⁷⁷Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK

⁷⁸Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK

⁷⁹Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta

⁸⁰Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University, 205 02, Sweden

⁸¹Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain

⁸²Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain

⁸³Department of Legal Medicine, University of Cantabria, Santander 39011, Spain

⁸⁴Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK

⁸⁵Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA

⁸⁶Department of Medicine and Physiology, McGill University, Montréal H4A 3J1, Canada

⁸⁷Department of Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA

⁸⁸Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel

⁸⁹Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA

⁹⁰Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA

⁹¹School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia

⁹²Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece

⁹³Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA

⁹⁴deCODE Genetics, Reykjavik IS-101, Iceland

⁹⁵Framingham Heart Study, Framingham, Massachusetts 01702, USA

⁹⁶Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal H3A 1A2, Canada

⁹⁷Department of Oncology, Gerald Bronfman Centre, McGill University, Montréal H2W 1S6, Canada

⁹⁸Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA

⁹⁹The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA

¹⁰⁰Department 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^1–8 as well as rare, population‐specific, coding variants⁹. 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 BMD⁸ (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., P_meta = 2 × 10⁻¹⁴), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10⁻¹¹; n_cases = 98,742 and n_controls = 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., P_meta = 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.

Links

DOI: 10.1038/nature14878

PubMed: 26367794

PubMedCentral: PMC4755714

WoS: 000362095100044

History

Received: 2014-04-28

Accepted: 2015-06-30

Online: 2015-09-14

Cited Works (1)

Year

Entry

2012

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2020	Song J, Zhang R, Lv L, Liang J, Wang W, Liu R, Dang X. The relationship between body mass index and bone mineral density: a Mendelian randomization study. Calcif Tiss Int. November 2020;107(5):440-445.
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2020	Manousaki D, Forgetta V, Keller‐Baruch J, Zhao K, Greenwood CMT, Mooser V, Bassett JHD, Leslie WD, Richards JB. A polygenic risk score as a risk factor for medication‐associated fractures. J Bone Miner Res. October 2020;35(10):1935-1941.
2021	Mun SH, Jastrzebski S, Kalinowski J, Zeng S, Oh B, Bae S, Eugenia G, Khan NM, Drissi H, Zhou P, Shin B, Lee S-K, Lorenzo J, Park-Min K-H. Sexual dimorphism in differentiating osteoclast precursors demonstrates enhanced inflammatory pathway activation in female cells. J Bone Miner Res. June 2021;36(6):1104-1116.
2022	Kasher M, Freidin MB, Williams FM, Cherny SS, Malkin I, Livshits G. Shared genetic architecture between rheumatoid arthritis and varying osteoporotic phenotypes. J Bone Miner Res. March 2022;37(3):440-453.
2022	Lu T, Forgetta V, Greenwood CMT, Richards JB. Identifying causes of fracture beyond bone mineral density: evidence from human genetics. J Bone Miner Res. August 2022;37(8):1592-1602.
2017	Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum A-T, Curry KF, White JK, Kussy F, Greenlaw KM, Xu C, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, Evans DM. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet. October 2017;49(10):1468-1475.
2021	Ho-Le TP, Tran HTT, Center JR, Eisman JA, Nguyen HT, Nguyen TV. Assessing the clinical utility of genetic profiling in fracture risk prediction: a decision curve analysis. Osteoporos Int. February 2021;32(2):271-280.
2021	Zhang Q, Greenbaum J, Shen H, Zhao L-J, Zhang W-D, Sun C-Q, Deng H-W. Detecting causal relationship between metabolic traits and osteoporosis using multivariable Mendelian randomization. Osteoporos Int. April 2021;32(4):715-725.
2016	Oei L. Epidemiological, Radiological and Genetic Aspects of Endocrine Bone Diseases [PhD thesis]. Erasmus University Rotterdam; December 14, 2016.
2019	Maynard RD. Establishing the Functional Role of Cped1* in the Genetic Regulation of the Osteoblast* [PhD thesis]. University of Rochester; 2019.