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

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

SUBMITTER: Grant AV

PROVIDER: S-EPMC3213022 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Grant Audrey V AV Boisson-Dupuis Stéphanie S Herquelot Eléonore E de Beaucoudrey Ludovic L Filipe-Santos Orchidée O Nolan Daniel K DK Feinberg Jacqueline J Boland Anne A Al-Muhsen Saleh S Sanal Ozden O Camcioglu Yildiz Y Palanduz Ayse A Kilic Sara Sebnem SS Bustamante Jacinta J Casanova Jean-Laurent JL Abel Laurent L

Journal of medical genetics 20110514 8

<h4>Introduction</h4>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.<h4>Methods</h4>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.< ...[more]

PMID: 21572128

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Project description:BACKGROUND: In families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD). Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data. METHODOLOGY/PRINCIPAL FINDINGS: The applicability and the effectiveness of HH in identifying the potential linkage of disease causative gene with high-density SNP genotype data were studied with a series of monogenic disorders ascertained in eastern Canadian populations. The HH approach was validated using the genotypes of patients from a family affected with a rare autosomal dominant disease Schnyder crystalline corneal dystrophy. HH accurately detected the approximately 1 Mb genomic interval encompassing the causative gene UBIAD1 using the genotypes of only four affected subjects. The successful application of HH to identify the potential linkage for a family with pericentral retinal disorder indicates that HH can be applied to perform family-based association analysis by treating affected and unaffected family members as cases and controls respectively. A new strategy for the genome-wide screening of known causative genes or loci with HH was proposed, as shown the applications to a myoclonus dystonia and a renal failure cohort. CONCLUSIONS/SIGNIFICANCE: Our study of the HH approach demonstrates that HH is very efficient and effective in identifying potential disease linked region. HH has the potential to be used as an efficient alternative approach to sequencing or microsatellite-based fine mapping for screening the known causative genes in genetic disease study.

Dataset Information

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

Publications

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

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