A test of transmission/disequilibrium for quantitative traits in pedigree data, by multiple regression.
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The transmission/disequilibrium (TD) test (TDT), proposed, by Spielman et al., for binary traits is a powerful method for detection of linkage between a marker locus and a disease locus, in the presence of allelic association. As a test for linkage disequilibrium, the TDT makes the assumption that any allelic association present is due to linkage. Allison proposed a series of TD-type tests for quantitative traits and calculated their power, assuming that the marker locus is the disease locus. All these tests assume that the observations are independent, and therefore they are applicable, as a test for linkage, only for nuclear-family data. In this report, we propose a regression-based TD-type test for linkage between a marker locus and a quantitative trait locus, using information on the parent-to-offspring transmission status of the associated allele at the marker locus. This method does not require independence of observations, thus allowing for analysis of pedigree data as well, and allows adjustment for covariates. We investigate the statistical power and validity of the test by simulating markers at various recombination fractions from the disease locus. (+info)
Selective sweep at the Drosophila melanogaster Suppressor of Hairless locus and its association with the In(2L)t inversion polymorphism.
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The hitchhiking model of population genetics predicts that an allele favored by Darwinian selection can replace haplotypes from the same locus previously established at a neutral mutation-drift equilibrium. This process, known as "selective sweep," was studied by comparing molecular variation between the polymorphic In(2L)t inversion and the standard chromosome. Sequence variation was recorded at the Suppressor of Hairless (Su[H]) gene in an African population of Drosophila melanogaster. We found 47 nucleotide polymorphisms among 20 sequences of 1.2 kb. Neutrality tests were nonsignificant at the nucleotide level. However, these sites were strongly associated, because 290 out of 741 observed pairwise combinations between them were in significant linkage disequilibrium. We found only seven haplotypes, two occurring in the 9 In(2L)t chromosomes, and five in the 11 standard chromosomes, with no shared haplotype. Two haplotypes, one in each chromosome arrangement, made up two-thirds of the sample. This low haplotype diversity departed from neutrality in a haplotype test. This pattern supports a selective sweep hypothesis for the Su(H) chromosome region. (+info)
Transmission disequilibrium test (TDT) when only one parent is available: the 1-TDT.
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The transmission disequilibrium test (TDT) is a useful method to locate mutations linked to disease genes associated with complex diseases. TDT requires genotypes of affected individuals and their parents. Recently, Ewens and Spielman (Am J Hum Genet 1998;62:450-8) extended the TDT for use in sibships with at least one affected and one unaffected individual and devised a new test called the sib transmission/disequilibrium test (S-TDT). The S-TDT can be applied to diseases with late age at onset such as non-insulin-dependent diabetes mellitus, psychiatric disorders, and diseases related to aging. For some disorders, it might be relatively easy to obtain the genotype of one parent either because the other parent is not available for study or he/she is not cooperative. Curtis and Sham (Ann Hum Genet 1995;59:323-36) showed that bias in transmitting certain alleles is introduced if only heterozygous parents and homozygous offspring are used in the TDT. In this paper, the authors propose a new test, the 1-TDT, to detect linkage between a candidate locus and a disease locus using genotypes of affected individuals and only one available parent for each affected individual. The test is not biased under the null hypothesis of no linkage or association. The authors validate their test using both simulated and real data sets. Finally, they show how to combine data from different types of families. (+info)
A common functional polymorphism (C-->A substitution at position -863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha.
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Tumour necrosis factor-alpha (TNF-alpha) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF-alpha has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The regulation of TNF-alpha expression in man is indicated to be partly genetically determined. We therefore screened a 1263 bp section of the proximal promoter of the TNF-alpha gene for common genetic variants affecting the transcriptional activity of the gene. Here we report the characterization of a common functional polymorphism in the promoter region of the TNF-alpha gene, a C-->A substitution at position -863. Electromobility shift assays provided evidence for a distinct difference in the binding of monocytic and hepatic nuclear factors to the -863C and -863A alleles. The rare -863A allele was associated with 31% lower transcriptional activity ( P < 0.001) in chloramphenicol acetyltransferase (CAT) reporter gene studies in human hepatoblastoma (HepG2) cells, indicating that the-863C/A polymorphism influences the basal rate of transcription of the TNF-alpha gene in vitro. Allele frequencies were 0.83/0.17 amongst 254 apparently healthy men of Swedish origin, aged 35-50 years. In 156 men, the -863C/A polymorphism was associated with the serum TNF-alpha concentration, carriers of the rare A allele having a significantly lower TNF-alpha level ( P < 0.05). It is concluded that the common-863C/A polymorphism in the promoter region of the TNF-alpha gene is functional in vitro in monocytic and hepatic cells and influences the serum TNF-alpha concentration in vivo in healthy middle-aged men. (+info)
Linkage and association of atopic asthma to markers on chromosome 13 in the Japanese population.
(37/5532)
Chromosome 13 contains several candidate genes for asthma and atopy, and markers on this chromosome have been shown to be linked to phenotypes of atopy or asthma in two genome-wide searches. We conducted a linkage study for atopic asthma using markers spanning the whole of chromosome 13 in Japanese families ascertained through asthmatic children and examined associations of atopic asthma with markers where linkage was suggested. Data were analysed using MAPMAKER/SIBS for the multipoint lod score (MLS) analysis and SIB-PAIR for the transmission dis-equilibrium test (TDT). Three peaks which exceeded a lod score of 1.0 were observed (MLS 2.4 between D13S175 and D13S217, MLS 2.0 between D13S153 and D13S156, and MLS 1.4 between D13S285 and D13S293). The global TDT for atopic asthma was significant for the marker D13S153 ( P = 0.0065) and the 96 bp allele of D13S153 was preferentially transmitted to atopic asthma-affected children ( P = 0.0009, Bonferroni correction 5% = 0. 0037, 1% = 0.00072). These findings indicate that genes on chromosome 13 may play an important role in the development of atopy or asthma across various populations. (+info)
High amounts of genetic differentiation between populations of the malaria vector Anopheles arabiensis from West Africa and eastern outer islands.
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Polymorphism at nine microsatellite loci was examined to assess the level of genetic differentiation between four Anopheles arabiensis populations from Senegal, the high plateau of Madagascar, and Reunion and Mauritius islands. Eight of nine loci showed great polymorphism (2-16 alleles/locus) and significant genetic differentiation was revealed between all four populations by F- and R-statistics, with Fst estimates ranging from 0.080 to 0.215 and equivalent Rst values ranging between 0.022 and 0.300. These high amounts of genetic differentiation are discussed in relation to geographic distance including large bodies of water, and history of mosquito settlement, and insecticide use on the islands. The results suggest that historical events of drift rather than mutation are probably the forces generating genetic divergence between these populations, with homogenization of the gene pool by migration being drastically restricted across the ocean. (+info)
An allele of COL9A2 associated with intervertebral disc disease.
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Intervertebral disc disease is one of the most common musculoskeletal disorders. A number of environmental and anthropometric risk factors may contribute to it, and recent reports have suggested the importance of genetic factors as well. The COL9A2 gene, which codes for one of the polypeptide chains of collagen IX that is expressed in the intervertebral disc, was screened for sequence variations in individuals with intervertebral disc disease. The analysis identified a putative disease-causing sequence variation that converted a codon for glutamine to one for tryptophan in six out of the 157 individuals but in none of 174 controls. The tryptophan allele cosegregated with the disease phenotype in the four families studied, giving a lod score (logarithm of odds ratio) for linkage of 4.5, and subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1. (+info)
Linkage disequilibrium and physical mapping of Pas1 in mice.
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By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a approximately 1.5-Mb region on distal mouse chromosome 6 the Pas1 locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1(s) susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1(s) allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene. (+info)