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J Med Genet. 2011 Aug;48(8):567-71. doi: 10.1136/jmg.2011.089128. Epub 2011 May 14.

Accounting for genetic heterogeneity in homozygosity mapping: application to Mendelian susceptibility to mycobacterial disease.

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  • 1Laboratoire de Génétique Humaine des Maladies Infectieuses, Université Paris Descartes-INSERM U980, Faculté de Médecine Necker, 156 rue de Vaugirard, Paris, France.

Abstract

INTRODUCTION:

Genome-wide homozygosity mapping is a powerful method for locating rare recessive Mendelian mutations. However, statistical power decreases dramatically in the presence of genetic heterogeneity.

METHODS:

The authors applied an empirical approach to test for linkage accounting for genetic heterogeneity by calculating the sum of positive per-family multipoint LOD scores (S) across all positions, and obtaining corresponding empirical p values (EmpP) through permutations.

RESULTS:

The statistical power of the approach was found to be consistently higher than the classical heterogeneity LOD by simulations. Among 21 first-cousin matings with a single affected child, for five families linked to a locus of interest and 16 families to other loci, S/EmpP achieved a power of 40% versus 28% for heterogeneity LOD at an α level of 0.001. The mean size of peak linkage regions was markedly higher for true loci than false positive regions. The S/EmpP approach was applied to a sample of 17 consanguineous families with Mendelian susceptibility to mycobacterial disease, leading to the identification of two mutations in IL12RB1 and TYK2 from the largest of six linkage regions at p<10(-3).

CONCLUSIONS:

The S/EmpP approach is a flexible and powerful approach that can be applied to linkage analysis of families with suspected Mendelian disorders.

PMID:
21572128
[PubMed - indexed for MEDLINE]
PMCID:
PMC3213022
Free PMC Article
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