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On the use of haplotype phylogeny to detect disease susceptibility loci.

Bardel C, Danjean V, Hugot JP, Darlu P, Génin E - BMC Genet. (2005)

Bottom Line: The idea is to search for clades with an excess of cases as compared to the whole sample and to identify the mutations defining these clades as potential candidate disease susceptibility sites.We show that under models where the susceptibility to the disease is caused by a single genetic variant, the cladistic test is neither really more powerful to detect an association nor really more efficient to localize the susceptibility site than an individual SNP testing.The use of phylogenies to group haplotypes is especially interesting to pinpoint the sites that are likely to be involved in disease susceptibility among the different markers identified within a gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unité de recherche en Génétique Epidémiologique et structure des populations humaines, INSERM U535, Villejuif, France. bardel@vjf.inserm.fr

ABSTRACT

Background: The cladistic approach proposed by Templeton has been presented as promising for the study of the genetic factors involved in common diseases. This approach allows the joint study of multiple markers within a gene by considering haplotypes and grouping them in nested clades. The idea is to search for clades with an excess of cases as compared to the whole sample and to identify the mutations defining these clades as potential candidate disease susceptibility sites. However, the performance of this approach for the study of the genetic factors involved in complex diseases has never been studied.

Results: In this paper, we propose a new method to perform such a cladistic analysis and we estimate its power through simulations. We show that under models where the susceptibility to the disease is caused by a single genetic variant, the cladistic test is neither really more powerful to detect an association nor really more efficient to localize the susceptibility site than an individual SNP testing. However, when two interacting sites are responsible for the disease, the cladistic analysis greatly improves the probability to find the two susceptibility sites. The impact of the linkage disequilibrium and of the tree characteristics on the efficiency of the cladistic analysis are also discussed. An application on a real data set concerning the CARD15 gene and Crohn disease shows that the method can successfully identify the three variant sites that are involved in the disease susceptibility.

Conclusion: The use of phylogenies to group haplotypes is especially interesting to pinpoint the sites that are likely to be involved in disease susceptibility among the different markers identified within a gene.

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Related in: MedlinePlus

Description of the nested clade analysis. (A) shows the homogeneity test performed at level k (between clades C1 and C2). If it is not significant (B), a test will be performed at the following level (k+1), between all the sub-clades descending from clades C1 and C2, i.e between clades C1.1, C1.2, C2.1 and C2.2 (3 degree of freedom). If it is significant the analysis ends because an association is detected.
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Figure 3: Description of the nested clade analysis. (A) shows the homogeneity test performed at level k (between clades C1 and C2). If it is not significant (B), a test will be performed at the following level (k+1), between all the sub-clades descending from clades C1 and C2, i.e between clades C1.1, C1.2, C2.1 and C2.2 (3 degree of freedom). If it is significant the analysis ends because an association is detected.

Mentions: Starting from the root of the tree, series of nested homogeneity tests comparing the number of cases and controls in different clades are performed. The principle of the method is explained in Figure 3. Briefly, at each level of the tree, homogeneity in the distribution of cases and controls is tested among all the n clades defined at this level. If the test is significant, an association is detected and the analysis ends. If the test is not significant, one homogeneity test is performed between all the sub-clades descending from the n clades.


On the use of haplotype phylogeny to detect disease susceptibility loci.

Bardel C, Danjean V, Hugot JP, Darlu P, Génin E - BMC Genet. (2005)

Description of the nested clade analysis. (A) shows the homogeneity test performed at level k (between clades C1 and C2). If it is not significant (B), a test will be performed at the following level (k+1), between all the sub-clades descending from clades C1 and C2, i.e between clades C1.1, C1.2, C2.1 and C2.2 (3 degree of freedom). If it is significant the analysis ends because an association is detected.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1173100&req=5

Figure 3: Description of the nested clade analysis. (A) shows the homogeneity test performed at level k (between clades C1 and C2). If it is not significant (B), a test will be performed at the following level (k+1), between all the sub-clades descending from clades C1 and C2, i.e between clades C1.1, C1.2, C2.1 and C2.2 (3 degree of freedom). If it is significant the analysis ends because an association is detected.
Mentions: Starting from the root of the tree, series of nested homogeneity tests comparing the number of cases and controls in different clades are performed. The principle of the method is explained in Figure 3. Briefly, at each level of the tree, homogeneity in the distribution of cases and controls is tested among all the n clades defined at this level. If the test is significant, an association is detected and the analysis ends. If the test is not significant, one homogeneity test is performed between all the sub-clades descending from the n clades.

Bottom Line: The idea is to search for clades with an excess of cases as compared to the whole sample and to identify the mutations defining these clades as potential candidate disease susceptibility sites.We show that under models where the susceptibility to the disease is caused by a single genetic variant, the cladistic test is neither really more powerful to detect an association nor really more efficient to localize the susceptibility site than an individual SNP testing.The use of phylogenies to group haplotypes is especially interesting to pinpoint the sites that are likely to be involved in disease susceptibility among the different markers identified within a gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unité de recherche en Génétique Epidémiologique et structure des populations humaines, INSERM U535, Villejuif, France. bardel@vjf.inserm.fr

ABSTRACT

Background: The cladistic approach proposed by Templeton has been presented as promising for the study of the genetic factors involved in common diseases. This approach allows the joint study of multiple markers within a gene by considering haplotypes and grouping them in nested clades. The idea is to search for clades with an excess of cases as compared to the whole sample and to identify the mutations defining these clades as potential candidate disease susceptibility sites. However, the performance of this approach for the study of the genetic factors involved in complex diseases has never been studied.

Results: In this paper, we propose a new method to perform such a cladistic analysis and we estimate its power through simulations. We show that under models where the susceptibility to the disease is caused by a single genetic variant, the cladistic test is neither really more powerful to detect an association nor really more efficient to localize the susceptibility site than an individual SNP testing. However, when two interacting sites are responsible for the disease, the cladistic analysis greatly improves the probability to find the two susceptibility sites. The impact of the linkage disequilibrium and of the tree characteristics on the efficiency of the cladistic analysis are also discussed. An application on a real data set concerning the CARD15 gene and Crohn disease shows that the method can successfully identify the three variant sites that are involved in the disease susceptibility.

Conclusion: The use of phylogenies to group haplotypes is especially interesting to pinpoint the sites that are likely to be involved in disease susceptibility among the different markers identified within a gene.

Show MeSH
Related in: MedlinePlus