The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies


Pereira, Lutécia H. Mateus, Pineda, Marbin A., Rowe, William H., Fonseca, Libia R., Greene, Mark H., Offit, Kenneth, Ellis, Nathan A., Zhang, Jinghui, Collins, Andrew and Struewing, Jeffery P. (2007) The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies. BMC Genetics, 8, (68) (doi:10.1186/1471-2156-8-68).

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Original Publication URL: http://dx.doi.org/10.1186/1471-2156-8-68

Description/Abstract

Background

We studied linkage disequilibrium (LD) patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done) using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient.

Results

BRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG).

Conclusion

Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations.

Item Type: Article
ISSNs: 1471-2156 (print)
Related URLs:
Keywords: single nucleotide, haplotypes, jews, sample size, case-control studies, founder effect, genes, laboratories, sequence deletion, polymorphism, brca1, cancer, humans, breast neoplasms
Subjects: H Social Sciences > HT Communities. Classes. Races
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Q Science > QH Natural history > QH426 Genetics
Divisions: University Structure - Pre August 2011 > School of Medicine > Developmental Origins of Health and Disease
ePrint ID: 60125
Date Deposited: 05 Sep 2008
Last Modified: 27 Mar 2014 18:42
URI: http://eprints.soton.ac.uk/id/eprint/60125

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