Interrogating Causal Effects of Body Composition and Puberty-Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two-Sample Mendelian Randomization Study.
Interrogating Causal Effects of Body Composition and Puberty-Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two-Sample Mendelian Randomization Study.
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青少年特发性脊柱侧凸（AIS）是儿童肌肉骨骼疾病最常见的形式。观察性研究指出了AIS的几个危险因素，但几乎没有证据支持它们与AIS的因果关系。在这里，我们应用孟德尔随机化（MR）来调查欧洲人和亚洲人的身体成分与青春期相关暴露和AIS风险之间的因果关系，孟德尔随机化（MR）已知可以限制混杂和反向因果关系的偏倚。对于我们的两样本MR研究，我们在大型欧洲全基因组关联研究（GWAS）中使用了与体重指数（BMI）、腰臀比、瘦质量、儿童肥胖、骨密度（BMD）、25 -羟基维生素D （25OHD）、月经初潮年龄和青春期生长相关的单核苷酸多态性（snp），并在日本生物银行（Biobank Japan）中使用了与成人骨质疏松症风险和月经初潮年龄相关的snp。我们从最大的多血统AIS GWAS的欧洲或亚洲亚群（N = 7956例/88,459例对照）中提取了上述AIS风险的snp估计。我们的反方差加权（IVW） MR估计结果表明，上述风险因素与AIS风险之间没有因果关系。多效性敏感MR方法也得到了类似的结果。然而，将我们的分析限制在患有AIS的欧洲女性，我们观察到估计的BMD与AIS风险之间存在因果关系（AIS的IVW优势比= 0.1,95%可信区间为0.01至0.7，估计BMD每增加SD p = 0.02），但在调整BMI、体脂质量和25OHD后，这种关联不再显著，在多变量mr中调整初月经年龄后，这种关联仍然显著。我们证明了BMD对欧洲血统女性AIS风险的保护性因果效应，但这种效应受到BMI、体脂量和25OHD水平的影响。未来的核磁共振研究需要使用更大的AIS GWAS来调查上述暴露对AIS的小影响。©2023作者。JBMR Plus由Wiley期刊有限责任公司代表美国骨骼和矿物研究协会出版。青少年特发性脊柱侧凸（AIS）是最常见的儿童肌肉骨骼疾病。观察性研究指出了AIS的几个危险因素，但几乎没有证据支持它们与AIS的因果关系。通过应用孟德尔随机化（MR）研究设计，我们证明了BMD对欧洲血统女性AIS风险的保护性因果效应，但这种效应受到BMI、体脂量和25OHD水平的影响。
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. Adolescent idiopathic scoliosis (AIS) is the most common 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. By applying a Mendelian randomization (MR) study design, 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.