Abstract
ABSTRACTGenetic 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 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Highlights
Osteoporosis is primarily an aging-related disease characterized by compromised bone strength that increases the risk of fracture
5’ untranslated region of the liver carboxylase 1 gene (CES1), which is expressed in the liver and whole blood[25] yet with no currently reported associations with bone mineral density (BMD) by Genome-wide association studies (GWAS) in the same chromosomal region (16q12.2) and with the nearest BMDassociated SNP mapping approximately 4 mega base pairs upstream at the SALL1 and CYLD locus.[26]. The calculated lambdas and QQ plots for the meta-analyses of femoral neck (FN) female and sex-combined analyses revealed no statistical inflation of the association p values
CpG site cg23196985 was found in the discovery meta-analysis to be strongly associated with FN BMD in females only and in analyses combining males and females, but upon validation in an extended sample that included related individuals, the association was attenuated in the female analysis and completely absent in sex-combined analyses
Summary
Osteoporosis is primarily an aging-related disease characterized by compromised bone strength that increases the risk of fracture. DNA methylation is known to play a role in gene expression and cell differentiation,(7,8) and differential DNA methylation has been linked to multiple human complex traits and disease phenotypes.[5,9,10,11,12] Studies performed using bone samples have identified epigenetic alterations that influence bone cell function.[13,14] We studied epigenetic variation in whole blood, as a proxy for difficult-to-acquire samples such as bone, in relation to BMD because epigenetic markers are often stable across multiple tissues, and immune cells within blood are known to influence bone homeostasis.[15] osteoclasts are derived from the monocyte-macrophage lineage found in whole blood.[16] epigenetic profiling has been performed previously in bone samples from osteoporotic and osteoarthritic patients[17] and an epigenome-wide association study (EWAS) of BMD has been performed in mice,(18) EWAS of BMD have not been reported in humans with validation of significant findings
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