Contribution of rare variation to degenerative orthopedic diseases

Degenerative orthopedic diseases (DODs) such as osteoporosis, osteoarthritis, spondylosis, spinal stenosis, and disc herniation are common disorders. Both common and rare genetic risk factors may contribute to DODs, but few large-scale whole-exome sequencing studies elucidating the contribution of rare variations to DODs have been published. The updated version of the Astra Zeneca portal (https://azphewas.com) was used to access gene collapsing analysis of rare variations for DODs.

One published UK Biobank portal: the updated Astra Zeneca portal based on whole genome sequencing (N = 484,111), was used to access gene collapsing analysis of rare qualifying variants (QVs) for fourteen DODs. A conservative threshold (p ≤ 5 × 10^-8) was used to decrease the risk of spurious associations. Odds ratios (ORs) with 95 % confidence intervals (CIs) were estimated.

One previously osteoporosis-linked gene (LRP5) was identified (p-value = 3.0 × 10^-13, OR = 1.55 (95%CI 1.38-1.73)). Two other significant genes were identified: the TET2 gene that was linked to dorsalgia (p-value = 8.3 × 10^-9, OR = 1.54 (95%CI 1.33-1.77)) and the SMAD6 gene that was associated with spinal stenosis (p-value = 1.7 × 10^-9, OR = 2.70 (95%CI 2.02-3.61)) and other spondylopathies (p-value = 9.0 × 10^-11, OR = 2.41 (95%CI 1.89-3.07)). Among controls 1.10 % were carriers of LRP5 QVs, 0.29 % of controls carried TET2 QVs, and 0.20 %-0.21 % of controls carried SMAD6 QVs.

One established osteoporosis gene (LRP5) and two other DODs genes (TET2 and SMAD6) were identified using gene collapsing analyses. Only a small number of genes reached the chosen significance threshold under the current phenotype definitions and analytic framework.