Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density

John A Morris; Pei-Chien Tsai; Roby Joehanes; Jie Zheng; Katerina Trajanoska; Mette Soerensen; Vincenzo Forgetta; Juan Edgar Castillo-Fernandez; Morten Frost; Tim D Spector; Kaare Christensen; Lene Christiansen; Fernando Rivadeneira; Jonathan H Tobias; David M Evans; Douglas P Kiel; Yi-Hsiang Hsu; J Brent Richards; Jordana T Bell

doi:10.1002/jbmr.3148

Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density

J Bone Miner Res. 2017 Aug;32(8):1644-1650. doi: 10.1002/jbmr.3148. Epub 2017 May 8.

Authors

John A Morris^{1

2}, Pei-Chien Tsai³, Roby Joehanes^{4

5}, Jie Zheng⁶, Katerina Trajanoska⁷, Mette Soerensen^{8

9}, Vincenzo Forgetta², Juan Edgar Castillo-Fernandez³, Morten Frost¹⁰, Tim D Spector³, Kaare Christensen^{8

9

11}, Lene Christiansen⁸, Fernando Rivadeneira⁷, Jonathan H Tobias^{6

12}, David M Evans^{6

13}, Douglas P Kiel^{4

5}, Yi-Hsiang Hsu^{4

5

14}, J Brent Richards^{1

2

3

15}, Jordana T Bell³

Affiliations

¹ Department of Human Genetics, McGill University, Montreal, Canada.
² Lady Davis Institute for Medical Research, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Canada.
³ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
⁴ Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.
⁵ Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁶ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁷ Departments of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands.
⁸ The Danish Twin Registry and The Danish Aging Research Center, Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
⁹ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁰ Endocrine Research Unit, KMEB, University of Southern Denmark, Odense, Denmark.
¹¹ Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
¹² Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
¹³ The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Departments of Epidemiology and Biostatistics and Medicine, McGill University, Montreal, Canada.

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 (N_Discovery = 4614, N_Validation = 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.

Keywords: BONE MINERAL DENSITY; DNA METHYLATION; EPIGENETICS; EPIGENOME-WIDE ASSOCIATION STUDY (EWAS); GENETIC EPIDEMIOLOGY.

Publication types

Multicenter Study
Randomized Controlled Trial
Twin Study

MeSH terms

Blood Cells / metabolism*
Bone Density*
CpG Islands*
DNA Methylation*
Epigenesis, Genetic*
Female
Femur Neck / metabolism
Genome-Wide Association Study
Humans
Male
Twins*

Abstract

Publication types

MeSH terms

Grants and funding