Adolescent idiopathic scoliosis (AIS) is the most common form of pediatric
musculoskeletal disorder. Observational studies have pointed to several
risk factors for AIS, but almost no evidence exists to support their causal
association with AIS. Here, we applied Mendelian randomization (MR), known
to limit bias from confounding and reverse causation, to investigate causal
associations between body composition and puberty-related exposures and AIS
risk in Europeans and Asians. For our two-sample MR studies, we used single
nucleotide polymorphisms (SNPs) associated with body mass index (BMI),
waist-hip ratio, lean mass, childhood obesity, bone mineral density (BMD),
25-hydroxyvitamin D (25OHD), age at menarche, and pubertal growth in large
European genome-wide association studies (GWAS), and with adult
osteoporosis risk and age of menarche in Biobank Japan. We extracted
estimates of the aforementioned SNPs on AIS risk from the European or Asian
subsets of the largest multiancestry AIS GWAS (N = 7956 cases/88,459 controls). The results of our inverse
variance-weighted (IVW) MR estimates suggest no causal association between
the aforementioned risk factors and risk of AIS. Pleiotropy-sensitive MR
methods yielded similar results. However, restricting our analysis to
European females with AIS, we observed a causal association between
estimated BMD and the risk of AIS (IVW odds ratio for AIS = 0.1, 95%
confidence interval 0.01 to 0.7, p = 0.02 per SD increase in estimated BMD), but this association was no
longer significant after adjusting for BMI, body fat mass, and 25OHD and
remained significant after adjusting for age at menarche in multivariable
MR. In conclusion, we demonstrated a protective causal effect of BMD on AIS
risk in females of European ancestry, but this effect was modified by BMI,
body fat mass, and 25OHD levels. Future MR studies using larger AIS GWAS
are needed to investigate small effects of the aforementioned exposures on
AIS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone
and Mineral Research.
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