Genetic architecture of lumbar spinal stenosis

Lumbar spinal stenosis (LSS) affects over 100 million people globally, with an increasing incidence due to an ageing population. While LSS is known to be heritable, its genetic basis remains poorly understood. We conduct a genome-wide meta-analysis of LSS in 40,303 cases and 741,469 controls. We identify 73 previously unreported loci in addition to 15 known loci, and highlight spinal degeneration as a key pathogenic mechanism. In 12,784 surgically treated cases, we discover five loci specifically associated with severe disease. Age-of-onset analyses show that most variants influence risk after midlife, but some confer susceptibility as early as age 34. Mendelian randomization further demonstrates causal effects of higher body mass and fat-free mass on LSS risk. Overall, our findings expand knowledge of the genetic background of LSS and inform future translational research.