Power Of Linkage Analysis Research Articles

Haplo2Ped: a tool using haplotypes as markers for linkage analysis

BackgroundGenerally, SNPs are abundant in the genome; however, they display low power in linkage analysis because of their limited heterozygosity. Haplotype markers, on the other hand, which are composed of many SNPs, greatly increase heterozygosity and have superiority in linkage statistics.ResultsHere we developed Haplo2Ped to automatically transform SNP data into haplotype markers and then to compute the logarithm (base 10) of odds (LOD) scores of regional haplotypes that are homozygous within the disease co-segregation haploid group. The results are reported as a hypertext file and a 3D figure to help users to obtain the candidate linkage regions. The hypertext file contains parameters of the disease linked regions, candidate genes, and their links to public databases. The 3D figure clearly displays the linkage signals in each chromosome. We tested Haplo2Ped in a simulated SNP dataset and also applied it to data from a real study. It successfully and accurately located the causative genomic regions. Comparison of Haplo2Ped with other existing software for linkage analysis further indicated the high effectiveness of this software.ConclusionsHaplo2Ped uses haplotype fragments as mapping markers in whole genome linkage analysis. The advantages of Haplo2Ped over other existing software include straightforward output files, increased accuracy and superior ability to deal with pedigrees showing incomplete penetrance. Haplo2Ped is freely available at: http://bighapmap.big.ac.cn/software.html.

A model for linkage analysis with apomixis

Apomixis, or asexual reproduction through seeds, occurs in over 400 species of angiosperms. Although apomixis can favorably perpetuate desired genotypes through successive seed generation, it may also bring about some difficulty for linkage analysis and quantitative trait locus mapping. In this article, we explore the issue of how apomixis affects the precision and power of linkage analysis with molecular markers. We derive a statistical model for estimating the linkage between different markers when some progeny are derived from apomixis. The model was constructed within the maximum likelihood framework and implemented with the EM algorithm. A series of procedures are formulated to test the linkage of markers, the rate of apomixis, and the degree of genetic interference during meiosis. The model was examined and validated through simulation studies. The model will provide a tool for linkage mapping and evolutionary studies for plant species that undergo apomixis.

Analytical estimation of the power of linkage analysis in large pedigrees

Different approaches to analytical calculation of the power in linkage analysis whose efficiencies have been demonstrated in small pedigrees are described. The possibility of applying them to large pedigrees has been estimated. Equivalence of the analytical estimates of power obtained using different approaches based on analysis of individual pairs of relatives has been shown. The accuracy of the resultant analytical estimation of the power has been analyzed for three large pedigrees and a wide range of quantitative trait inheritance models; the accuracy has been demonstrated to be sufficiently high and equal to the accuracy in the case of small pedigrees.

A genome-wide Asian genetic map and ethnic comparison: The GENDISCAN study

BackgroundGenetic maps provide specific positions of genetic markers, which are required for performing genetic studies. Linkage analyses of Asian families have been performed with Caucasian genetic maps, since appropriate genetic maps of Asians were not available. Different ethnic groups may have different recombination rates as a result of genomic variations, which would generate misspecification of the genetic map and reduce the power of linkage analyses.ResultsWe constructed the genetic map of a Mongolian population in Asia with CRIMAP software. This new map, called the GENDISCAN map, is based on genotype data collected from 1026 individuals of 73 large Mongolian families, and includes 1790 total and 1500 observable meioses. The GENDISCAN map provides sex-averaged and sex-specific genetic positions of 1039 microsatellite markers in Kosambi centimorgans (cM) with physical positions. We also determined 95% confidence intervals of genetic distances of the adjacent marker intervals.Genetic lengths of the whole genome, chromosomes and adjacent marker intervals are compared with those of Rutgers Map v.2, which was constructed based on Caucasian populations (Centre d'Etudes du Polymorphisme Humain (CEPH) and Icelandic families) by mapping methods identical to those of the GENDISCAN map, CRIMAP software and the Kosambi map function. Mongolians showed approximately 1.9 fewer recombinations per meiosis than Caucasians. As a result, genetic lengths of the whole genome and chromosomes of the GENDISCAN map are shorter than those of Rutgers Map v.2. Thirty-eight marker intervals differed significantly between the Mongolian and Caucasian genetic maps.ConclusionThe new GENDISCAN map is applicable to the genetic study of Asian populations. Differences in the genetic distances between the GENDISCAN and Caucasian maps could facilitate elucidation of genomic variations between different ethnic groups.

Linkage analysis of anti-CCP levels as dichotomized and quantitative traits using GAW15 single-nucleotide polymorphism scan of NARAC families

Rheumatoid arthritis is a clinically and genetically heterogeneous disease. Anti-cyclic citrullinated (anti-CCP) antibodies have a high specificity for rheumatoid arthritis and levels correlate with disease severity. The focus of this study was to examine whether analyzing anti-CCP levels could increase the power of linkage analysis by identifying a more homogeneous subset of rheumatoid arthritis patients. We also wanted to compare linkage signals when analyzing anti-CCP levels as dichotomized (CCP_binary), categorical (CCP_cat), and continuous traits, with and without transformation (log_CCP and CCP_cont). Illumina single-nucleotide polymorphism scans of the North American Rheumatoid Arthritis Consortium families were analyzed for four chromosomes (6, 7, 11, 22) using nonparametric linkage (NPL) (rheumatoid arthritis and CCP_binary), regress (CCP_cat and Log_CCP), and deviates (CCP_cont) analysis options as implemented in Merlin. Similar linkage results were obtained from analyses of rheumatoid arthritis, CCP_binary, and CCP_cont. The only exception was that we observed improved linkage signals and a narrower region for CCP_binary as compared to a clinical diagnosis of rheumatoid arthritis alone on chromosome 7, a region which previously showed variation in linkage results with rheumatoid arthritis according to anti-CCP levels. Analyses of CCP_cat and Log_CCP had little power to detect linkage. Our data suggested that linkage analyses of anti-CCP levels may facilitate identification of rheumatoid arthritis genes but quantitative analyses did not further improve power. Our study also highlighted that quantitative trait linkage results are highly sensitive to phenotype transformation and analytic approaches.

New susceptibility locus for hypertension on chromosome 8q by efficient pedigree-breaking in an Italian isolate

Essential hypertension (EH) affects a large proportion of the adult population in Western countries and is a major risk factor for cardiovascular diseases. EH is a multifactorial disease with a complex genetic component. To tackle the complexity of this genetic component, we have initiated a study of Campora, an isolated village in South Italy. A random sample of 389 adults was genotyped for a very dense microsatellite genome scan and phenotyped for EH. Of this sample, 173 affected individuals were all related through a 2,180-member pedigree and could be integrated within a linkage analysis. The complexity of the pedigree prevented its direct use for a non-parametric linkage (NPL) analysis. Therefore, the method proposed by Falchi et al. [2004, Am. J. Hum. Genet., 75, 1015-1031] was used for automatic pedigree-breaking. We identified a new locus for EH on chromosome 8q22-23 and detected linkage with two known loci for EH: 1q42-43 and 4p16. Simulations showed that the linkage with 8q22-23 is highly genome-wide significant, even when accounting for the breaking of the pedigree. An extension to qualitative traits of another pedigree-breaking approach [Pankratz et al., 2001, Genet. Epidemiol., 21 (Suppl. 1), S258-S263] also detected a significant linkage on 8q22-23 using a remarkably different set of sub-pedigrees and helped to refine the location of the linkage signal. This work both identifies a new locus strongly linked to hypertension and shows that the power of linkage analysis can be improved by the appropriate use of efficient pedigree-breaking strategies.

Phenotypic features of familial febrile seizures: case-control study.

To identify phenotypic features of febrile seizures that can be used to reduce heterogeneity and thereby increase power in linkage analysis. Despite exciting discoveries in several rare pedigrees, the genetic basis of common febrile seizures remains a mystery. The major drawback of studying common febrile seizure disorder is etiologic and genetic heterogeneity. A linkage sample must therefore be classified a priori on phenotypic criteria likely to reflect genetically homogeneous subgroups. Eighty-three cases (children with one or more febrile seizure plus first-degree family history of febrile seizures) and 101 controls (children with one or more febrile seizure but no first-degree family history of febrile seizures) were compared for association of phenotypic features in an unmatched case-control design. Odds ratios were calculated using univariate and multivariate methods. Recurrent febrile seizures was the only phenotypic feature significantly associated with first-degree family history of febrile seizures (OR 2.1, 95% CI 1.15 to 3.88). First-degree family history and later occurrence of afebrile seizures (OR 3.47, 95% CI 0.94 to 12.78) were independently associated with recurrent febrile seizures. Complex features did not show familial aggregation. The authors suggest recurrent and afebrile seizures as criteria on which to subgroup a linkage sample. These subgroups will not be evident at the time of the initial febrile seizure. Meticulous and prospective collection of phenotypic and family data are recommended.

Genetic Analysis Workshop II: results of incorporating a linkage disequilibrium parameter.

The corporation of a linkage disequilibrium parameter, delta, into linkage analysis is illustrated for data from Genetic Analysis Workshop II. Points from a joint likelihood surface are calculated and displayed on a recombination fraction-linkage disequilibrium grid using a simple modification of LIPED. The approach is shown to increase the power of linkage analysis and the power of tests for heterogeneity of linkage for the simulated examples.