Identification of a Psoriasis Susceptibility Candidate Gene by Linkage Disequilibrium Mapping with a Localized Single Nucleotide Polymorphism Map

Hewett, Duncan R.; Samuelsson, Lena; Polding, Joanne; Enlund, Fredrik; Smart, Devi H.; Cantone, Kathryn L.; See, Chee Gee; Chadha, Sapna; Inerot, Annica; Enerbäck, Charlotta; Montgomery, Douglas S.; Christodolou, Chris; Robinson, Phil; Matthews, Paul M.; Plumpton, Mary; Dykes, Colin W.; Wahlström, Jan; Swanbeck, G; Martinsson, Tommy; Roses, Allen D.; Riley, John; Purvis, Ian J.

doi:10.1006/geno.2002.6720

Cited by 99 publications

(69 citation statements)

References 39 publications

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“…Of the remaining 90 SNPs, 38 mapped to a 400 kb, region on chromosome 22, 32 24 to a region on chromosome 19, 30 and 28 to a region on chromosome 3. 31 A subset of 313 SNPs, whose minor allele frequencies were 45%, was selected for the estimation of deviation from HWE. A total of 36 SNPs (11.5%), with minor allele frequencies ranging between 0.06 and 0.49, were found to deviate from HWE (Po0.05) ( Table 3).…”

Section: Resultsmentioning

confidence: 99%

Detection of genotyping errors by Hardy–Weinberg equilibrium testing

et al. 2004

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Genotyping data sets may contain errors that, in some instances, lead to false conclusions. Deviation from Hardy-Weinberg equilibrium (HWE) in random samples may be indicative of problematic assays. This study has analysed 107 000 genotypes generated by TaqMan, RFLP, sequencing or mass spectrometric methods from 443 single-nucleotide polymorphisms (SNPs). These SNPs are distributed both within genes and in intergenic regions. Genotype distributions for 36 out of 313 assays (11.5%) whose minor allele frequencies were 40.05 deviated from HWE (Po0.05). Some of the possible reasons for this deviation were explored: assays for five SNPs proved nonspecific, and genotyping errors were identified in 21 SNPs. For the remaining 10 SNPs, no reasons for deviation from HWE were identified. We demonstrate the successful identification of a proportion of nonspecific assays, and assays harbouring genotyping error. Consequently, our current high-throughput genotyping system incorporates tests for both assay specificity and deviation from HWE, to minimise the genotype error rate and therefore improve data quality.

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Section: Resultsmentioning

confidence: 99%

Detection of genotyping errors by Hardy–Weinberg equilibrium testing

et al. 2004

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“…SLC12A8 was the first candidate gene to be investigated in this region and it encodes a potassium/chloride transporter . Hewett et al 31 have reported an association between SLC12A8 variants and psoriasis in 148 Swedish nuclear families but failed to replicate their findings in 47 multi-affected families. A subsequent study 32 failed to replicate the SLC12A8 association in 210 German nuclear families, showing only bordeline association with the SLC12A8 rs2228674 marker (P ¼ 0.048).…”

Section: Discussionmentioning

confidence: 95%

“…16 The PS-risk haplotype is a 5 SNP-marker haplotype identified by Hewett et al 31 using SNP markers and TDT analysis, within the 3q21 region; however no disease-causing function has been attributed to the gene (SLC12A8), including the intronic SNPs. 31 In this study we therefore focused on a gene (ie CSTA) located within the psoriasis susceptibility region on chromosome 3q21, but outside the 5-SNP marker haplotypes as previously defined. 31 It is possible that the PS risk haplotype defined by Hewett et al 31 is a part of an extended haplotype which does include CSTA TCC.…”

Section: Discussionmentioning

confidence: 99%

“…31 In this study we therefore focused on a gene (ie CSTA) located within the psoriasis susceptibility region on chromosome 3q21, but outside the 5-SNP marker haplotypes as previously defined. 31 It is possible that the PS risk haplotype defined by Hewett et al 31 is a part of an extended haplotype which does include CSTA TCC. SLC12A8 was the first candidate gene to be investigated in this region and it encodes a potassium/chloride transporter .…”

Section: Discussionmentioning

confidence: 99%

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Association analysis of the skin barrier gene cystatin A at the PSORS5 locus in psoriatic patients: evidence for interaction between PSORS1 and PSORS5

et al. 2008

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Family-based analysis has revealed several loci for psoriasis and the locus, PSORS5, on chromosome 3q21 has been found in two independent studies. In this region, cystatin A (CSTA) encodes a skin barrier cystein protease inhibitor found in human sweat and it is over-expressed in psoriatic skin. Three CSTA markers at positions -190 (g.À190T4C), þ 162 (c.162T4C) and þ 344 (c.344C4T) were analysed in 107 unrelated patients and 216 matched controls. There was a significant trend for association with CSTA c.162T4C and psoriasis (odds ratio (OR) ¼ 3.45, Po0.001). Analysis of constructed haplotypes showed a highly significant association between disease and CSTA -190T/ þ 162C/ þ 344C (CSTA TCC) (P ¼ 10 À6 ). In independent study, a TDT analysis in 126 nuclear families confirmed the over-transmission of CSTA TCC (P ¼ 0.0001). The presence of statistical interaction between CSTA TCC haplotype and HLA-Cw6 at PSORS1 locus was detected by performing TDT analysis on CSTA haplotypes stratified by the presence or absence of the risk allele at HLA-Cw6 locus. To estimate the disease risk we employed conditional logistic regression on the family data. The CSTA TCC haplotype is only associated with psoriasis in those individuals carrying the risk allele at the HLA-Cw6 locus (OR ¼ 2.22, P ¼ 0.0004, 95% CI ¼ 1.42, 3.49). These results represent a major step towards the dissection of genetic factors involved in the pathogenesis of psoriasis.

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“…disease associated variant at GABRB3, there are reports of effects that persist hundreds of kilobases from a presumed susceptibility allele. 55,60 Finally, although observations of transmission disequilibrium at multiple SNPs within the same gene argue against type I error, these data have not been corrected for multiple comparisons. Since appropriate methods for correction are currently unavailable for nonindependent comparisons as with markers in LD, ultimate interpretation will rely heavily on independent replication and further genetic analysis of ATP10C.…”

Section: Discussionmentioning

confidence: 99%

Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism

et al. 2003

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Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5 0 introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11-q13.

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Identification of a Psoriasis Susceptibility Candidate Gene by Linkage Disequilibrium Mapping with a Localized Single Nucleotide Polymorphism Map

Cited by 99 publications

References 39 publications

Detection of genotyping errors by Hardy–Weinberg equilibrium testing

Detection of genotyping errors by Hardy–Weinberg equilibrium testing

Association analysis of the skin barrier gene cystatin A at the PSORS5 locus in psoriatic patients: evidence for interaction between PSORS1 and PSORS5

Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism

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