Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.
Medina-Gomez C., Kemp JP., Trajanoska K., Luan J., Chesi A., Ahluwalia TS., Mook-Kanamori DO., Ham A., Hartwig FP., Evans DS., Joro R., Nedeljkovic I., Zheng H-F., Zhu K., Atalay M., Liu C-T., Nethander M., Broer L., Porleifsson G., Mullin BH., Handelman SK., Nalls MA., Jessen LE., Heppe DHM., Richards JB., Wang C., Chawes B., Schraut KE., Amin N., Wareham N., Karasik D., Van der Velde N., Ikram MA., Zemel BS., Zhou Y., Carlsson CJ., Liu Y., McGuigan FE., Boer CG., Bønnelykke K., Ralston SH., Robbins JA., Walsh JP., Zillikens MC., Langenberg C., Li-Gao R., Williams FMK., Harris TB., Akesson K., Jackson RD., Sigurdsson G., den Heijer M., van der Eerden BCJ., van de Peppel J., Spector TD., Pennell C., Horta BL., Felix JF., Zhao JH., Wilson SG., de Mutsert R., Bisgaard H., Styrkársdóttir U., Jaddoe VW., Orwoll E., Lakka TA., Scott R., Grant SFA., Lorentzon M., van Duijn CM., Wilson JF., Stefansson K., Psaty BM., Kiel DP., Ohlsson C., Ntzani E., van Wijnen AJ., Forgetta V., Ghanbari M., Logan JG., Williams GR., Bassett JHD., Croucher PI., Evangelou E., Uitterlinden AG., Ackert-Bicknell CL., Tobias JH., Evans DM., Rivadeneira F.
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.