Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Am J Hum Genet
Authors
Keywords
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Year of Publication
2018
Journal
Am J Hum Genet
Volume
102
Issue
1
Pages
88-102
Date Published
2018 01 04
ISSN
1537-6605
DOI
10.1016/j.ajhg.2017.12.005
PubMed ID
29304378
PubMed Central ID
PMC5777980
Links
Grant list
MR/N003284/1 / MRC_ / Medical Research Council / United Kingdom
U01 HL130114 / HL / NHLBI NIH HHS / United States
UL1 TR002369 / TR / NCATS NIH HHS / United States
G1000143 / MRC_ / Medical Research Council / United Kingdom
R01 AG005407 / AG / NIA NIH HHS / United States
MC_UU_12013/4 / MRC_ / Medical Research Council / United Kingdom
MR/M004422/1 / MRC_ / Medical Research Council / United Kingdom
P30 CA016058 / CA / NCI NIH HHS / United States
R01 AG027574 / AG / NIA NIH HHS / United States
U01 AR066160 / AR / NIAMS NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
648916 / ERC_ / European Research Council / International
G0401527 / MRC_ / Medical Research Council / United Kingdom