Fine-mapping and resequencing studies following up significant linkage signals on chromosomes 7 and 10  

This study builds on work started in the mid-1990s by the UK-based Oxford Endometriosis Gene (OXEGENE) Study (Stephen Kennedy, NDOG) and the Australian Genes Behind Endometriosis Study (Susan Treloar, Queensland Institute for Medical Research - QIMR, Australia), who recruited families with multiple affected members for genetic linkage studies. Combined analysis of the two datasets, comprising a total of 1,176 families, showed significant linkage to chromosome 10q26 (MLS = 3.09) and 7p13-15 (MOD: 3.30).

With Grant Montgomery (QIMR, Australia), we were funded by the National Institutes of Health (US) to fine-map the 20 Mb region of interest on chromosome 10. A very dense set of common single nucleotide polymorphisms (SNPs) selected to cover the region, supplemented by all known rare gene-based SNPs, were genotyped using a custom Illumina array in 1,200 familial cases and 1,200 controls, and significant SNPs tested for replication in an additional 2,500 cases and 2,500 controls. Results suggested an association with variants close to CYP2C19 (PubMed: 21497341), a finding which is being followed up through resequencing studies.

 

image001

Linkage signal on chromosome 10. Am J Hum Genet 2005; 77: 365-6.

 

 

 

 

 

The linkage signal on chromosome 7 suggested the influence of one or more rare genetic variants with near-Mendelian inheritance. This linkage signal was replicated in an analysis of an extended pedigree of rhesus macaques with spontaneous endometriosis in the US. To try and identify the underlying rare variants, we conducted a resequencing study in 8 women with endometriosis from the families most contributing to the signal, using Nimblegen Sequence Capture and Roche 454 Genome Sequencing, and are currently following up results through sequencing in larger datasets of both women and rhesus macaques.

 

image002

        Linkage signal on chromosome 7. Hum Reprod 2007; 22: 717-28