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

Isabelle Schrauwen; 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

doi:10.1016/j.ajhg.2009.01.023

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

Journal article

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

Isabelle Schrauwen, Megan Ealy, Matthew J Huentelman, Melissa Thys, Nils Homer, Kathleen Vanderstraeten, Erik Fransen, Jason J Corneveaux, David W Craig, Mireille Claustres, …

American journal of human genetics, Vol.84(3), pp.328-338

03/2009

DOI: 10.1016/j.ajhg.2009.01.023

PMCID: PMC2667982

PMID: 19230858

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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.

Genome-Wide Association Study

Extracellular Matrix Proteins - biosynthesis

Serine Endopeptidases - biosynthesis

Extracellular Matrix Proteins - genetics

Humans

Male

Nerve Tissue Proteins - genetics

Case-Control Studies

Cell Adhesion Molecules, Neuronal - genetics

Otosclerosis - metabolism

Ear, Inner - metabolism

Cell Adhesion Molecules, Neuronal - biosynthesis

Nerve Tissue Proteins - biosynthesis

Serine Endopeptidases - genetics

Female

Otosclerosis - genetics

Polymorphism, Single Nucleotide

Genome, Human

Details

Title: Subtitle: A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis
Creators: Isabelle Schrauwen - Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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 - Mount Sinai Hospital
Erwin Offeciers
Richard J H Smith - University of Iowa, Otolaryngology
Guy Van Camp
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.84(3), pp.328-338
DOI: 10.1016/j.ajhg.2009.01.023
PMID: 19230858
PMCID: PMC2667982
NLM abbreviation: Am J Hum Genet
ISSN: 0002-9297
eISSN: 1537-6605
Publisher: Elsevier; United States
Grant note: T32 GM008629 / NIGMS NIH HHS
Language: English
Date published: 03/2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984024894502771

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