Massively parallel characterization of adolescent idiopathic scoliosis risk variants

While a significant genetic component to AIS is recognized, the functional impact of most associated genetic variants, particularly those in non-coding regions, remains largely unknown. Using massively parallel reporter assays, we characterize 1,664 variant positions in linkage disequilibrium with 26 AIS lead variants identified by genome-wide association studies (GWAS) in chondrocytes, a major cell type implicated in AIS pathogenesis.

Using a library of 7,173 candidate regulatory sequences we compare the 1,664 reference alleles against 4,708 alternate alleles in two human chondrocyte cell lines (TC28a2 and SW1353). Our analysis identifies 92 variants that exhibit significant differential regulatory activity between their reference and alternate alleles, 79 of which are predicted to disrupt transcription factor binding sites, often correlating with their observed regulatory effect.