Cortical structural variations and scoliosis risk: insights from a large-scale Mendelian randomization analysis

Scoliosis is a complex condition that may be influenced by neurobiological factors, including brain structure. Does a causal relationship exist between brain structure and scoliosis, and if so, which brain structural imaging-derived phenotypes (IDPs) are implicated? We conducted a bidirectional Mendelian randomization (MR) analysis to evaluate potential causal relationships between brain structural IDPs and scoliosis. Instrumental variables were selected from genome-wide association studies, and causal estimates were derived primarily using inverse variance weighted (IVW) analysis, complemented by other sensitivity analyses. In the forward MR analysis, 27 brain structural IDPs showed positive associations with scoliosis risk, whereas 37 showed negative associations. Notably, increased grey matter volume in the left middle frontal gyrus (MFG) showed the strongest association (IDP code: IDP_T1_FAST_ROIs_L_mid_front_gyrus; IVW OR=2.238, 95% CI: 1.534–3.264, P=2.911×10 -5 ; P_FDR=0.049), and it remained significant after FDR correction. In the reverse MR analysis, scoliosis was associated with 55 brain structural traits, but none remained significant after FDR correction. These findings provide evidence supporting a potential causal role of specific brain structures in scoliosis susceptibility, particularly the left MFG, a region associated with postural control. Further studies are needed to replicate these associations and clarify their clinical relevance. • Bidirectional MR was used to explore causality between brain structure and scoliosis • Increased grey matter volume in the left middle frontal gyrus linked to scoliosis risk • Scoliosis showed no causal effect on the same brain region in reverse MR analysis • Findings suggest cortical involvement in postural control may underlie scoliosis risk • Results highlight the value of neuroimaging-genetic integration in scoliosis research