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SNP Haplotypes (snp + haplotype)
Selected AbstractsSibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic densityGENETIC EPIDEMIOLOGY, Issue 4 2010J. Stone Abstract Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software. Genet. Epidemiol. 34: 309,318, 2010. © 2009 Wiley-Liss, Inc. [source] ATM mutations on distinct SNP and STR haplotypes in ataxia-telangiectasia patients of differing ethnicities reveal ancestral founder effects,HUMAN MUTATION, Issue 1 2003Catarina Campbell Abstract Due to the large size (150 kb) of the ataxia-telangiectasia mutated (ATM) gene and the existence of over 400 mutations, identifying mutations in patients with ataxia-telangiectasia (A-T) is labor intensive. We compared the SNP and STR haplotypes of A-T patients from varying ethnicities who were carrying common ATM mutations. We used SSCP to determine SNP haplotypes. To our surprise, all of the most common ATM mutations in our large multiethnic cohort were associated with specific SNP haplotypes, whereas the STR haplotypes varied, suggesting that ATM mutations predated STR haplotypes but not SNP haplotypes. We conclude that these frequently observed ATM mutations are not hot spots, but have occurred only once and spread with time to different ethnic populations. More generally, a combination of SNP and STR haplotyping could be used as a screening strategy for identifying mutations in other large genes by first determining the ancestral SNP and STR haplotypes in order to identify specific founder mutations. We estimate this approach will identify approximately 30% of mutations in A-T patients across all ethnic groups. Hum Mutat 21:80,85, 2002. © 2002 Wiley-Liss, Inc. [source] The importance of haplotype length and heritability using genomic selection in dairy cattleJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 1 2009T.M. Villumsen Summary Reliabilities for genomic estimated breeding values (GEBV) were investigated by simulation for a typical dairy cattle breeding setting. Scenarios were simulated with different heritabilites (h2) and for different haplotype sizes, and seven generations with only genotypes were generated to investigate reliability of GEBV over time. A genome with 5000 single nucleotide polymorphisms (SNP) at distances of 0.1 cM and 50 quantitative trait loci (QTL) was simulated, and a Bayesian variable selection model was implemented to predict GEBV. Highest reliabilities were obtained for 10 SNP haplotypes. At optimal haplotype size, reliabilities in generation 1 without phenotypes ranged from 0.80 for h2 = 0.02 to 0.93 for h2 = 0.30, and in the seventh generation without phenotypes ranged from 0.69 for h2 = 0.02 to 0.86 for h2 = 0.30. Reliabilities of GEBV were found sufficiently high to implement dairy selection schemes without progeny testing in which case a data time-lag of two to three generations may be present. Reliabilities were also relatively high for low heritable traits, implying that genomic selection could be especially beneficial to improve the selection on, e.g. health and fertility. [source] The probability that similar haplotypes are identical by descentANNALS OF HUMAN GENETICS, Issue 3 2002I. M. NOLTE The logic of gene mapping in highly penetrant diseases is to find the minimal overlap of haplotypes that are identical by descent (IBD). If the pedigree is unknown, identity by descent of haplotype overlap cannot be established with certainty. In many cases, it is intuitively clear that similar haplotypes are indeed IBD. The logical and statistical evaluation of haplotype overlap requires that probabilities of IBD are substantial. It is, therefore, important to estimate these probabilities. In this paper, we derive a recursive formula for the probability of IBD. Simulations are used to validate the expected values and to study the variability around the expected value. We demonstrate that for populations 1000 generations of age , without bottlenecks , haplotypes of 1 cM consisting of at least five microsatellite markers have a significant probability to be IBD. Likewise, SNP haplotypes of 1 cM should consist of at least nine identical SNP alleles for a similar probability of IBD. Without considering bottlenecks, haplotypes consisting of as few as three SNPs spanning a region of less than 0.01 cM are likely IBD in populations that are 10000 generations of age. [source] Association of the FAM167A,BLK region with systemic sclerosisARTHRITIS & RHEUMATISM, Issue 3 2010Ikue Ito Objective An association of single-nucleotide polymorphisms (SNPs) in the FAM167A (previously referred to as C8orf13),BLK region with systemic lupus erythematosus (SLE) has been demonstrated in Caucasians and in Asians. Recent studies have shown that many genes, including IRF5, STAT4, and PTPN22, are shared susceptibility genes in multiple autoimmune diseases. We undertook the current study to examine whether the FAM167A,BLK region is also associated with susceptibility to systemic sclerosis (SSc). Methods Japanese patients with SSc (n = 309) and healthy controls (n = 769) were enrolled in a 2-tiered case,control association study. In tier 1, 124 patients and 412 controls were tested to determine association of 16 tag SNPs encompassing the FAM167A,BLK region with SSc. In tier 2, an additional 185 patients and 357 controls were analyzed for SNP rs13277113. Results Two haplotype blocks that correspond approximately to FAM167A and BLK were observed. In tier 1 of the study, the rs13277113A allele in the BLK block exhibited the most significant association with SSc after correction for multiple testing (permutated P = 0.024). Two SNP haplotypes formed by rs13277113 and the most significant SNP in the FAM167A block did not exhibit stronger association. When samples from tier 1 and tier 2 were combined, the rs13277113A allele was significantly associated with SSc (odds ratio 1.45 [95% confidence interval 1.17,1.79], P = 6.1 × 10,4). Association or a tendency toward association of rs13277113A with SSc was observed regardless of a patient's autoantibody profile or whether a patient had diffuse cutaneous or limited cutaneous SSc. Conclusion Our findings indicate that the rs13277113A allele is associated not only with SLE but also with SSc and that the FAM167A,BLK region is a common genetic risk factor for both SLE and SSc. 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