Title: Genetically Determined Later Puberty Impacts Lowered Bone Mineral Density in Childhood and Adulthood.
Authors: Cousminer, Diana L; Mitchell, Jonathan A; Chesi, Alessandra; Roy, Sani M; Kalkwarf, Heidi J; Lappe, Joan M; Gilsanz, Vicente; Oberfield, Sharon E; Shepherd, John A; Kelly, Andrea; McCormack, Shana E; Voight, Benjamin F; Zemel, Babette S; Grant, Struan Fa
Published In J Bone Miner Res, (2018 Mar)
Abstract: Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR). The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta ± SE = -0.078 ± 0.024; p = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes. Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site- and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. © 2017 American Society for Bone and Mineral Research.
PubMed ID: 29068475
MeSH Terms: Adult; Age Factors; Bone Density/genetics*; Child; Female; Genetic Predisposition to Disease*; Humans; Male; Mendelian Randomization Analysis; Multifactorial Inheritance/genetics; Puberty/genetics*; Risk Factors; Time Factors