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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

Comparison of the efficiency to localize the two susceptibility sites between CT and SbST. The efficiency to localize the two susceptibility sites is measured by the percentage of replicates in which the two sites are detected (black circles) or at least one of the two sites (white circles) Each symbol corresponds to one of the ten tree topologies. (A): penetrance 0.9 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes; (B): penetrance 0.6 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes.
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Figure 2: Comparison of the efficiency to localize the two susceptibility sites between CT and SbST. The efficiency to localize the two susceptibility sites is measured by the percentage of replicates in which the two sites are detected (black circles) or at least one of the two sites (white circles) Each symbol corresponds to one of the ten tree topologies. (A): penetrance 0.9 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes; (B): penetrance 0.6 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes.

Mentions: The efficiency of SbST, CT and CLADHC to localize the susceptibility site(s) when it is included among the SNPs is presented in Figure 1 and 2. The efficiency of CT is plotted against the efficiency of SbST or CLADHC. To correctly interpret these figures, it has to be noted that the criteria used to compare the methods are not strictly identical. Indeed, the identified SNP is always unambiguously detected by the SbST method, since this is the site giving the most significant chi-square and two chi-squares are never exactly identical. On the other hand, the susceptibility site may not be the only one detected by CT because two or more sites could have the same values of the criteria (Vi, see the Methods section). However, in our simulations, the susceptibility site is the only one detected in from 80% (for 1 tree) to 100% (for 5 trees) of the replicates. When the susceptibility site is not found alone, it is almost always found with only one other site, rarely with two other sites (<0.5% of the replicates).


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

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

Comparison of the efficiency to localize the two susceptibility sites between CT and SbST. The efficiency to localize the two susceptibility sites is measured by the percentage of replicates in which the two sites are detected (black circles) or at least one of the two sites (white circles) Each symbol corresponds to one of the ten tree topologies. (A): penetrance 0.9 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes; (B): penetrance 0.6 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Comparison of the efficiency to localize the two susceptibility sites between CT and SbST. The efficiency to localize the two susceptibility sites is measured by the percentage of replicates in which the two sites are detected (black circles) or at least one of the two sites (white circles) Each symbol corresponds to one of the ten tree topologies. (A): penetrance 0.9 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes; (B): penetrance 0.6 for homozygotes carrying the two susceptibility alleles and 0.3 for all other genotypes.
Mentions: The efficiency of SbST, CT and CLADHC to localize the susceptibility site(s) when it is included among the SNPs is presented in Figure 1 and 2. The efficiency of CT is plotted against the efficiency of SbST or CLADHC. To correctly interpret these figures, it has to be noted that the criteria used to compare the methods are not strictly identical. Indeed, the identified SNP is always unambiguously detected by the SbST method, since this is the site giving the most significant chi-square and two chi-squares are never exactly identical. On the other hand, the susceptibility site may not be the only one detected by CT because two or more sites could have the same values of the criteria (Vi, see the Methods section). However, in our simulations, the susceptibility site is the only one detected in from 80% (for 1 tree) to 100% (for 5 trees) of the replicates. When the susceptibility site is not found alone, it is almost always found with only one other site, rarely with two other sites (<0.5% of the replicates).

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