New paper out
We just got a new paper out yesterday in BMC Medical Genetics:
Schierup et al.
BMC Medical Genetics 2009, 10:20 doi:10.1186/1471-2350-10-20
Abstract
Background
A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers.
Methods
We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk.
Results
We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the Fst value) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping.
Conclusions
The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.
Mikkel and I got involved in the project to try to use our haplotype based association mapping methods to analyse data where a single marker analysis had already shown an association with several kinds of cancer.
We didn’t really discover anything new when running our tools on the data, so to try something else we combined the case/control data with HapMap data to try to increase the number of markers through imputation.
That is when we discovered that a haplotype in the region, that is found in about 50% of Europeans (CEU and our case/control data) is only found in ~1% of Africans (YRI). Furthermore, this haplotype was the at-risk haplotype in our case/control data and looks to be the derived haplotype when compared with the chimp genome.
Reference
Mikkel H Schierup, Thomas Mailund, Heng Li, Jun Wang, Anne Tjonneland, Ulla Vogel, Lars Bolund, Bjorn A Nexo (2009). Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups BMC Medical Genetics, 10 (1) DOI: 10.1186/1471-2350-10-20
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