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. 2009 Mar;84(3):328-38.
doi: 10.1016/j.ajhg.2009.01.023. Epub 2009 Feb 19.

A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis

Isabelle Schrauwen  1 , Megan Ealy, Matthew J Huentelman, Melissa Thys, Nils Homer, Kathleen Vanderstraeten, Erik Fransen, Jason J Corneveaux, David W Craig, Mireille Claustres, Cor W R J Cremers, Ingeborg Dhooge, Paul Van de Heyning, Robert Vincent, Erwin Offeciers, Richard J H Smith, Guy Van Camp
Affiliations

A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis

Isabelle Schrauwen et al. Am J Hum Genet. 2009 Mar.

Abstract

Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis.

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Figures

Figure 1
Figure 1
Schematic Representation of the Staged Design Used in This Study
Figure 2
Figure 2
Fine Mapping of the chr7q22.1 Region in the Belgian-Dutch Population Significance is spread over the whole region. The strength of LD (r2 value) is shown in shades of gray. The originally identified SNP is indicated by an asterisk. The LD structure is based on CEPH genotype data (HapMap release 21a, phase II).
Figure 3
Figure 3
Fine Mapping of the chr11q13.1 Region in the Belgian-Dutch Population All of the significance is located in the region of high LD telomeric to the original SNP (right LD block). The strength of LD (r2 value) is shown in shades of gray. The originally identified SNP is indicated by an asterisk. Seventeen genes or gene predictions are located in this region (based on NCBI build 36). The LD structure is based on CEPH genotype data (HapMap release 21a, phase II).
Figure 4
Figure 4
Reelin Expression in Inner Ear and Stapes Footplate (A) RT-PCR analysis of P6 mouse cochlea (membranous part). P denotes postnatal day. (B) RT-PCR analysis of adult human stapes footplates. (C) Western blot analysis of P28 mouse brain and the complete inner ear (including surrounding cartilage). The arrow head indicates a nonspecific band detected by the secondary antibody.
Figure 5
Figure 5
Expression Levels of Reln in Mice at Different Time Points after Birth P denotes postnatal day. The error bars indicate SEM.
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