Interrogating Causal Effects of Body Composition and Puberty-Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two-Sample Mendelian Randomization Study

Faegheh Ghanbari, Nao Otomo, Isabel Gamache, Takuro Iwami, Yoshinao Koike, Anas M. Khanshour, Shiro Ikegawa, Carol A. Wise, Chikashi Terao, Despoina Manousaki

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere10830
JournalJBMR Plus
Volume7
Issue number12
DOIs
StatePublished - Dec 2023

Keywords

  • ADOLESCENT IDIOPATHIC SCOLIOSIS
  • BODY MASS INDEX
  • BONE MINERAL DENSITY
  • GENOME-WIDE ASSOCIATION STUDY
  • MENDELIAN RANDOMIZATION

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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