412 Genetic Variants Underlying Expression of ADPRM and CAB39 Confer Susceptibility for Lumbar Disc Degeneration

INTRODUCTION: Lumbar disc degeneration is heritable, with twin studies estimating a heritability of up to 74%. Despite family history explaining a substantial proportion of variance in incidence, severity, and progression, little is known about the genetic variants underlying risk and how they functionally contribute to disease. METHODS: We applied transcriptomic imputation methods to identify tissue-specific drivers of lumbar disc degeneration from static genotypes. We applied skeletal muscle and spinal cord-specific transcriptomic imputation models (from the GTEx consortium) to the BioMe Biobank (n=32,031), including 1,166 individuals with lumbar disc degeneration. We tested the transcriptome-wide association of imputed expression with lumbar disc degeneration using age, sex, and the first 10 genotype-derived principal components as covariates. Significance was determined using p-values corrected for multiple testing correction using the Benjamini Hochberg false discovery rate FDR<0.05. RESULTS: In the cervical spinal cord, downregulation of ADPRM and upregulation of the lncRNA LA16c-325D7.2 were significantly associated with lumbar disc degeneration (p= 4.39x10-5 and 2.12x10-5, respectively). These genes have known roles in modulation of oxidative stress and immune signaling. In skeletal muscle, CAB39upregulation (p=1.35x10-5), a known macrophage activator involved in chondrocyte dynamics, was associated with lumbar disc degeneration. In particular, the rs188317175 variant underlying CAB39 gene expression, and the rs139086394 variant underlying ADPRM expression were associated with lumbar disc degeneration (p=6.16x10-3 and p= 1.62x10-5, respectively). CONCLUSIONS: Genes involved in immune signaling, oxidative stress, and structural remodeling are associated with genetic risk for lumbar disc degeneration in the spinal cord and muscle, and may represent targets of therapeutic intervention or genetic screening to better identify and treat susceptible individuals.