Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessingSPP1andLTBP4variants
J.C. van den BergenMonika HillerStefan BöhringerLinda VijfhuizenHendrika B. GinjaarAmina ChaouchKate BushbyVolker StraubMariacristina ScotoSebahattin ÇirakVéronique HumbertclaudeMireille ClaustresC. ScottonChiara PassarelliHanns LochmüllerFrancesco MuntoniSylvie Tuffery‐GiraudAlessandra FerliniAnnemieke Aartsma‐RusJan J.G.M. VerschuurenPeter A.C. ‘t HoenPietro Spitali
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Abstract:
Objective
Duchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials.Methods
Duchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates.Results
We show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss.Conclusions
This study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials.Keywords:
SNP
Linkage Disequilibrium
Genetic Association
Association studies may request more details of a specific haplotype. Haplotype-specific decay of linkage disequilibrium is such a crucial and versatile characteristic. It may be used, e.g. to search for signals of natural selection in a risk haplotype. Here, we present a web-based tool to explore the relationship between population frequency and extended linkage disequilibrium measured as haplotype homozygosity of observed haplotypes within a specified candidate region.The web-tool is available at http://ihg.gsf.de/cgi-bin/mueller/webehh.pl
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HLA haplotype frequency was studied by typing 201 members of 32 unrelated families. Linkage disequilibrium was determined by observed and expected haplotype frequencies. The two-locus haplotype frequencies with most significant linkage disequilibrium were A30-B13, Aw33-B17, Bw46-Cw11, B12-Cw8, A1-Cw6 and A33-Cw3. No locus recombination was noted among 137 children.
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Abstract: Juvenile idiopathic arthritis (JIA) is an HLA‐associated rheumatic disease with onset in childhood. We recently reported that allele 5 at microsatellite D6S265 in the HLA class I region is associated with JIA, independent of linkage disequilibrium with the high risk DR8‐DQ4 haplotype. In the present study, we investigated whether alleles at D6S265, or other markers in this region, also modify the risk for JIA on other haplotypes, i.e., DRB1*1301‐DQB1*0603 or DRB1*1101/4‐DQB1*0301. We observed a significant association with allele 6 at D6S265 on the DRB1*1301‐DQB1*0603 haplotype. We also noted an association with allele 3 at D6S265, when carried on the DRB1*1101/4‐DQB1*0301 haplotype. Our results further support an additional JIA susceptibility gene in the HLA class I region in linkage disequilibrium with alleles at D6S265.
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Summary Genome wide association studies (GWAS) have largely succeeded family-based linkage studies in livestock and human populations as the preferred method to map loci for complex or quantitative traits. However, the type of results produced by the two analyses contrast sharply due to differences in linkage disequilibrium (LD) imposed by the design of studies. In this paper, we demonstrate that association and linkage studies are in agreement provided that (i) the effects from both studies are estimated appropriately as random effects, (ii) all markers are fitted simultaneously and (iii) appropriate adjustments are made for the differences in LD between the study designs. We demonstrate with real data that linkage results can be predicted by the sum of association effects. Our association study captured most of the linkage information because we could predict the linkage results with moderate accuracy. We suggest that the ability of common single nucleotide polymorphism (SNP) to capture the genetic variance in a population will depend on the effective population size of the study organism. The results provide further evidence for many loci of small effect underlying complex traits. The analysis suggests a more informed method for GWAS is to fit statistical models where all SNPs are analysed simultaneously and as random effects.
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Present studies examined the DNA polymorphisms in the AGT genes in a Chinese population in Henan province of central China. By using PCR-RFLP and maximum likelihood estimation (MLE), we estimated the pattern of intragenic linkage disequilibrium and the haplotype structure and explored the possible association between the polymorphisms of AGT gene and essential hypertension in a case-control study. Seven polymorphic sites (SNPs) and seven major haplotypes of AGT gene were analyzed. Among the individual SNP pairs examined, the A-6G, C+31T and M235T are nearly completely disequilibrium. All those single polymorphism loci were individually not associated with hypertension. But we found the frequency of haplotype H2 (-217: G, -152: G, -20: A, -6: G, +31: T, 174: T, 235: M) was significantly higher in controls than patients (P=0.010). Our study suggested that few haplotypes derived seven polymorphism loci could account for the most of the variation in AGT gene in Chinese Hans. The haplotype H2 of AGT gene might represent or be in disequilibrium with a genetic protective factor against EH.
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This chapter contains sections titled: Introduction Linkage Disequilibrium Mapping Genes Using Linkage Disequilibrium Tests for Association Analysis of Haplotype Data Association Tests for Quantitative Traits Association and Genomic Screening Special Populations Summary References
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Abstract Complex diseases affect a substantial proportion of the human population and are caused by multiple genetic and environmental effects. The association study is a means of identifying genetic variation that may be involved in complex disease etiology. The existence of linkage disequilibrium (nonrandom association of alleles) across the human genome can be used to reduce the number of variants needed to successfully correlate with phenotypic traits. We discuss the current status and problems inherent in performing whole genome association studies to analyze complex diseases.
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