Front Endocrinol (Lausanne). 2026 Aug 7;17:1876849. doi: 10.3389/fendo.2026.1876849. eCollection 2026.
ABSTRACT
INTRODUCTION: Adolescent idiopathic scoliosis (AIS) affects 2% to 3% of adolescents and progresses rapidly during puberty. Previous studies suggest that a positive family history of AIS and a later age at menarche (AAM) are risk factors for curve severity in AIS, but their quantitative evidence and the causal contribution of AAM remain to be elucidated.
METHODS: We analyzed 5,891 patients with AIS to evaluate the associations of family history and AAM with curve severity. Genetic correlation, Mendelian randomization, harmonized variant-level analyses, and variance component analyses were also performed.
RESULTS: Family history was associated with curve severity (β = 1.26, P = 0.024), and this association showed a dose-dependent relationship (β = 1.31, P = 0.006). Later AAM was linearly associated with greater curve severity (β = 1.95, P = 3.7 × 10-23). AAM showed genetic correlation with Cobb angle (r_g = 0.25, P = 0.04), but not with susceptibility to AIS (r_g = 0.04, P = 0.33), suggesting distinct contributions of AAM to AIS susceptibility and curve severity. Mendelian randomization provided suggestive evidence for an effect of later AAM on curve severity, with no evidence of horizontal pleiotropy. Harmonized variant-level analyses showed that AIS susceptibility alleles tended to have concordant positive effects on curve severity. A variance component analysis demonstrated that AAM and family history explained 2.7% and 0.2% of the variance in Cobb angle, respectively.
DISCUSSION: This study provides quantitative genetic evidence linking family history of AIS and later AAM to curve severity. These findings support the use of family history and AAM in clinical settings to stratify patients according to the risk of greater curve severity.
PMID:42630198 | PMC:PMC13493220 | DOI:10.3389/fendo.2026.1876849
