Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Nat Commun. 2022 Feb 2;13(1):634. doi: 10.1038/s41467-022-28167-1.

Abstract

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Bone and Bones / metabolism
  • Genome-Wide Association Study
  • Humans
  • Intervertebral Disc / metabolism*
  • Intervertebral Disc Degeneration / genetics*
  • Intervertebral Disc Displacement / genetics*
  • Sodium Sulfate Cotransporter / genetics*
  • Sodium Sulfate Cotransporter / metabolism*
  • Sulfates / metabolism*
  • Symporters / genetics
  • Symporters / metabolism

Substances

  • 3' Untranslated Regions
  • SLC13A1 protein, human
  • Sodium Sulfate Cotransporter
  • Sulfates
  • Symporters
  • sodium sulfate

Supplementary concepts

  • Intervertebral disc disease