A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

Abstract

In this study we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults.We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests.After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed association of very rare variants in the 3'-UTR with the phenotype.The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with a strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex 4 diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study

“…This suggest both protective and disease-causing variants are associated with otosclerosis. These findings are in line with previous studies, where also protective and disease-causing variants have been described in otosclerosis [ 16 , 19 , 32 ]. In the two other genes, EYA2 and TGFβ1 , no variants were found that were significantly associated with otosclerosis after multiple testing correction.…”

“…Patients and controls, collected for the purpose of genetic research in otosclerosis and used in previous studies, were used and no additional samples were collected for this current study. The cohort was used in the past to study associations of different genes with otosclerosis (e.g., TGFβ1 , BMP2 , BMP4 , RELN and COL1A1 ) [ 19 , 20 , 21 , 22 ] and for targeted resequencing of MEPE , SERPINF1 and ACAN [ 16 , 17 , 23 ].…”

“…224 smMIPs were designed using MIPgen [ 24 ] and ordered from IDT (Integrated DNA Technologies) (Coralville, IA, USA). smMIP enrichment was performed similarly to previous described protocols [ 16 , 17 , 25 ].…”

“…Several association studies have been performed, where analysis of common variants in functional candidate genes identified associated variants in different genes such as TGFβ1 , RELN , COL1A1 , BMP2 and BMP4 . Targeted resequencing of candidate genes has identified new pathogenic variants in genes as MEPE and ACAN [ 16 , 17 ].…”

The risks of RELN polymorphisms and its expression in the development of otosclerosis

“…Several case-control studies reported a significant association of SNPs in COL1A1 [ 6 , 7 ] , TGF-β1 [ 8 , 9 ] , BMP2 [ 10 ], BMP4 [ 7 , 10 ] and OPG [ 11 , 12 ] genes with OTSC in different populations. Recently, high throughput sequencing has spotted certain pathogenic variants in MEPE , ACAN and SERPINF1 genes with unsettled pathogenicity [ 5 , 13 ].…”