The Impact of Brain Morphometry on Low Back Pain Risk: A Mendelian Randomization Study.

Background: Low back pain (LBP) is a major global health concern with genetic and central nervous system factors. Recent studies have indicated associations between brain morphometry and LBP, but the causal relationships remain unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of brain morphometric features on LBP, leveraging genome-wide association study (GWAS) summary statistics. Genetic instruments for cortical structure were obtained from the ENIGMA consortium, while instruments for regional brain volumes were derived from UK Biobank imaging data; sulcal morphology traits were obtained from a large neuroimaging GWAS. LBP summary statistics were sourced from the FinnGen consortium. The inverse variance weighted (IVW) method was used as the primary analysis, complemented by multiple sensitivity analyses, including MR-Egger regression, weighted median estimation, and MR-PRESSO, to evaluate the core MR assumptions and assess robustness. Results: After false discovery rate correction, ten brain morphometric traits were identified as being causally associated with LBP. These associations primarily involved greater global cortical surface area and larger volumes in frontal and temporal regions, the cingulate cortex, and the thalamus, indicating consistent protective effects. In contrast, no causal associations were observed for sulcal morphology traits. Conclusion: Genetically reduced global cortical surface area and frontal-thalamic brain volumes were causally associated with an increased risk of LBP, providing novel evidence for a central neuroanatomical contribution to pain vulnerability.