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Significant evidence for linkage to chromosome 5q13 in a genome-wide scan for asthma in an extended pedigree resource.

ABSTRACT: Asthma is a multifactorial disease with undetermined genetic factors. We performed a genome-wide scan to identify predisposition loci for asthma. The asthma phenotype consisted of physician-confirmed presence or absence of asthma symptoms. We analyzed 81 extended Utah pedigrees ranging from three to six generations, including 742 affected individuals, ranging from 2 to 40 per pedigree. We performed parametric multipoint linkage analyses with dominant and recessive models. Our analysis revealed genome-wide significant evidence of linkage to region 5q13 (log of the odds ratio (LOD)=3.8, recessive model), and suggestive evidence for linkage to region 6p21 (LOD=2.1, dominant model). Both the 5q13 and 6p21 regions indicated in these analyses have been previously identified as regions of interest in other genome-wide scans for asthma-related phenotypes. The evidence of linkage at the 5q13 region represents the first significant evidence for linkage on a genome-wide basis for this locus. Linked pedigrees localize the region to approximately between 92.3-105.5 Mb.

SUBMITTER: Teerlink CC

PROVIDER: S-EPMC2672963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genome-wide linkage scan for maximum and length-dependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3.

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Linkage and linkage disequilibrium scan for autism loci in an extended pedigree from Finland.

Project description:Population isolates, such as Finland, have proved beneficial in mapping rare causative genetic variants due to a limited number of founders resulting in reduced genetic heterogeneity and extensive linkage disequilibrium (LD). We have here used this special opportunity to identify rare alleles in autism by genealogically tracing 20 autism families into one extended pedigree with verified genealogical links reaching back to the 17th century. In this unique pedigree, we performed a dense microsatellite marker genome-wide scan of linkage and LD and followed initial findings with extensive fine-mapping. We identified a putative autism susceptibility locus at 19p13.3 and obtained further evidence for previously identified loci at 1q23 and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at 19p13 and ATP1A2 at 1q23.

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Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q.

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Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13.

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Genome-wide scan for hypertension linkage to chromosome 12q23.1 - q23.3 in a Chinese family.

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Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22.

Project description:Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.

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Genome-wide linkage scan of a pedigree with familial hypercholesterolemia suggests susceptibility loci on chromosomes 3q25-26 and 21q22.

Project description:BackgroundFamilial hypercholesterolemia (FH) is a heritable disorder that can increase the risk of premature coronary heart disease. Studies suggest there are substantial genetic heterogeneities for different populations. Here we tried to identify novel susceptibility loci for FH in a Chinese pedigree.Methodology/principal findingsWe performed a SNP-based genome-wide linkage scan with the Chinese FH pedigree. Two suggestive linkage loci not previously reported were identified on chromosomes 3q25.1-26.1 (NPL = 9.01, nominal P<0.00001, and simulated occurrence per genome scan = 1.08) and 21q22.3 (NPL = 8.95, nominal P<0.00001, and simulated occurrence per genome scan = 1.26). In the interaction analysis with a trimmed version of the pedigree, we obtained a significantly increased joint LOD score (2.70) compared with that obtained when assuming the two loci uncorrelated, suggesting that more than one locus was involved in this pedigree. Exon screening of two candidate genes ABCG1 and LSS from one of the suggestive region 21q22 didn't report any causative mutations.Conclusions/significancesThese results confirm complex etiologies and suggest new genetic casual factors for the FH disorder. Further study of the two candidate regions is advocated.

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Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene.

Project description:Asthma is a complex genetic disorder. Many studies have suggested that chromosome 12q harbours a susceptibility gene for asthma and atopy. Linkage on chromosome 12q24.21-q24.33 was investigated in 167 Danish families with asthma.A two step procedure was used: (1) a genome-wide scan in one set of families followed by (2) fine scale mapping in an independent set of families in candidate regions with a maximum likelihood score (MLS) of > or =1.5 in the genome-wide scan. Polymorphisms in a candidate gene in the region on 12q24.33 were tested for association with asthma in a family based transmission disequilibrium test.An MLS of 3.27 was obtained at 12q24.33. The significance of this result was tested by simulation, resulting in a significant empirical genome-wide p value of 0.018. To our Knowledge, this is the first significant evidence for linkage on chromosome 12q, and suggests a candidate region distal to most previously reported regions. Three single nucleotide polymorphisms in splicing factor, arginine/serine-rich 8 (SFRS8) had an association with asthma (p < or = 0.0020-0.050) in a sample of 136 asthmatic sib pairs. SFRS8 regulates the splicing of CD45, a protein which, through alternative splice variants, has an essential role in activating T cells. T cells are involved in the pathogenesis of atopic diseases such as asthma, so SFRS8 is a very interesting candidate gene in the region.Linkage and simulation studies show that the very distal part of chromosome 12q contains a gene that increases the susceptibility to asthma. SFRS8 could act as a weak predisposing gene for asthma in our sample.

| S-EPMC2104763 | biostudies-literature

Significant linkage evidence for a predisposition gene for pelvic floor disorders on chromosome 9q21.

Project description:Predisposition factors for pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress urinary incontinence (SUI), urge urinary incontinence (UUI), and hernias, are not well understood. We assessed linkage evidence for PFDs in mostly sister pairs who received treatment for moderate-to-severe POP. We genotyped 70 affected women of European descent from 32 eligible families with at least two affected cases by using the Illumina 1 million single-nucleotide polymorphism (SNP) marker set. Parametric linkage analysis with general dominant and recessive models was performed by the Markov chain Monte Carlo linkage analysis method, MCLINK, and a set of SNPs was formed, from which those in high linkage disequilibrium were eliminated. Significant genome-wide evidence for linkage was identified on chromosome 9q21 with a HLOD score of 3.41 under a recessive model. Seventeen pedigrees (53%) had at least nominal evidence for linkage on a by-pedigree basis at this region. These results provide evidence for a predisposition gene for PFDs on chromosome 9q.

| S-EPMC2681003 | biostudies-literature

A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4.

Project description:Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.

| S-EPMC56990 | biostudies-literature

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