Genetic variants in the RELN gene are associated with otosclerosis in multiple European populations

Abstract

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is considered a complex disease caused by both genetic and environmental factors. In a previous study, we identified a region on chr7q22.1 located in the RELN gene that is associated with otosclerosis in Belgian-Dutch and French populations. Evidence for allelic heterogeneity was found in this chromosomal region in the form of two independent signals. To confirm this finding, we have completed a replication study that includes four additional populations from Europe (1,141 total samples). Several SNPs in this region replicated in these populations separately. While the power to detect significant association in each population is small, when all four populations are combined, six of seven SNPs replicate and show an effect in the same direction as in the previous populations. We also confirmed the presence of allelic heterogeneity in this region. These data further implicate RELN in the pathogenesis of otosclerosis. Functional research is warranted to determine the pathways through which RELN acts in the pathogenesis of otosclerosis.

Genetic variants in RELN are associated with otosclerosis in a non‐European population from Tunisia

“…The effect size (OR: 3.055 [1.487-6.277]) was in the same direction as previously found (Schrauwen et al, 2009b). Associations between otosclerosis and SNPs in RELN and on chr11q13.1 were previously reported in several independent populations from European origin (Schrauwen et al, 2009a(Schrauwen et al, , 2009b. We performed a meta-analysis for SNPs that were significantly associated with otosclerosis or showed a trend towards association (p < 0.1) in the Tunisian population.…”

“…These four SNPs are located in two regions (ch7q22.1 and chr11q13.1) that were recently discovered in a GWAS using pooled DNA samples and replicated in two independent European populations (Schrauwen et al, 2009b). The region on chr7q22.1, which is located in intron 1 to 4 of the RELN gene, was confirmed further by replication in four additional European populations (Schrauwen et al, 2009a). In this study, we show that these associations with otosclerosis are also present in a population of non-European origin.…”

“…The first region, on chr7q22.1, is located in the Reelin (RELN) gene. A further replication study in four other European populations has replicated the association of the RELN gene with otosclerosis (Schrauwen et al, 2009a). However, its role in the development of the disease is not obvious because there is currently no known role for reelin in bone metabolism.…”

“…Seven SNPs on chromosome 7q22.1 located in the RELN gene and four SNPs on chromosome 11q13.1 were selected for genotyping based on association data from previous studies (Schrauwen et al, 2009a). Genotyping was done by Kbioscience (Hoddesdon, UK).…”

“…If the interaction term was significant, meaning that sex has an influence on the effect of the SNP, females and males were tested separately. Meta-analysis was performed on all SNPs with a p-value below 0.1 in the Tunisian population, combining all studied populations (Belgian-Dutch, French, Italian, German, Swiss, Romanian, and Tunisian) (Schrauwen et al, 2009a(Schrauwen et al, , 2009b. In a logistic regression framework, we first tested for homogeneity of genetic effects across all populations by including an interaction term genotype x origin into the model.…”