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Open Access Methodology article

Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

Peter Brooks1*, Charles Marcaillou1, Maud Vanpeene1, Jean-Paul Saraiva1, Daniel Stockholm2, Stephan Francke3, Reyna Favis3, Nadine Cohen3, Francis Rousseau1, Frédéric Tores1, Pierre Lindenbaum1, Jörg Hager1 and Anne Philippi1

Author Affiliations

1 IntegraGen SA, 4 rue Pierre Fontaine, 91000 Evry, France

2 Généthon, CNRS UMR8115, 1 rue de l'Internationale, Evry 91000, France

3 Department of Pharmacogenomics, Johnson & Johnson PRD, PO Box 300, Raritan, New Jersey 08869, USA

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BMC Genetics 2009, 10:16  doi:10.1186/1471-2156-10-16

Published: 30 March 2009

Abstract

Background

The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI.

Results

We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis.

Conclusion

Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing.