title: Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density.
abstract: Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals (NDiscovery= 4614, NValidation= 901). We associated methylation at multiple cytosine-phosphate-guanine (CpG) sites with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD. We performed sex-combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false-discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10-11) and 4614 females and males (p = 3.0 × 10-8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large-effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.|Lady Davis Institute for Medical Research, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Morris
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.|Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Departments of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Katerina
authors.initials: K
authors.lastname: Trajanoska
authors.affiliation: The Danish Twin Registry and The Danish Aging Research Center, Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.|Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Soerensen
authors.affiliation: Lady Davis Institute for Medical Research, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Forgetta
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Juan Edgar
authors.initials: JE
authors.lastname: Castillo-Fernandez
authors.affiliation: Endocrine Research Unit, KMEB, University of Southern Denmark, Odense, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Frost
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: The Danish Twin Registry and The Danish Aging Research Center, Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.|Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: The Danish Twin Registry and The Danish Aging Research Center, Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
authors.affiliation: Departments of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Tobias
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.|Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.|Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.|Lady Davis Institute for Medical Research, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Canada.|Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.|Departments of Epidemiology and Biostatistics and Medicine, McGill University, Montreal, Canada.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
mesh_terms: D001773:Blood Cells / Q000378:metabolism*; D015519:Bone Density; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005272:Femur Neck / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D014427:Twins
keywords: BONE MINERAL DENSITY; DNA METHYLATION; EPIGENETICS; EPIGENOME-WIDE ASSOCIATION STUDY (EWAS); GENETIC EPIDEMIOLOGY