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At least 145 records · Page 8Linked to original sources
PubMed2005

Multilocus linkage disequilibrium mapping by the decay of haplotype sharing with samples of related individuals.

We consider the problem of multilocus linkage disequilibrium (LD) mapping of a trait-associated variant from case-control samples in which some individuals may be related. Our method, which we call DHS-R, is an extension of the decay of haplotype sharing (DHS) method of McPeek and Strahs and Strahs and McPeek. The DHS-R method shares the main features of the DHS method: (1) it allows construction of a confidence interval for the location of a trait-associated variant; (2) it allows for missing observations and unphased genotype data, with the uncertainty in the haplotypes taken into account in the analysis; and (3) it allows for heterogeneity, mutation, recombination, and background LD. The main advances of the DHS-R are (1) the ability to include individuals of arbitrary known relationship (including inbreeding) in the case and control samples; (2) an extension to allow partially-phased haplotypes derived from case-parent trio genotype data; and (3) an extension to allow for genotyping error in the model. Our method, which uses a hidden Markov model for likelihood calculation and maximization, has the advantage of being computationally feasible even in a large, complex pedigree. Simulations based on a 13-generation, 1,623-member Hutterite pedigree demonstrate accurate coverage of the confidence intervals for location of the variant. We apply the method to fine-mapping of a susceptibility locus for bronchial hyperresponsiveness (BHR) in the Hutterites. The results confirm the importance of taking into account the relatedness of individuals in LD mapping.

Algorithms↗
PubMed1997

Genetic polymorphism and recombination in the subtelomeric region of chromosome 14q.

Subtelomeric regions of human chromosomes are the sites of increased meiotic recombination and have a male-to-female recombination ratio that is higher than elsewhere in the genome. We isolated two novel, polymorphic CA repeat markers from the distal part of the immunoglobulin heavy chain gene cluster, approximately 90 and 200 kb from the telomere of chromosome 14q. The 14q telomere was unambiguously located by physical mapping of telomeric YACs and Bal31 exonuclease digestion of genomic DNA. We then constructed haplotypes using genotype data from these markers and data from sCAW1 (D14S826) for use as a highly polymorphic genetic marker. Linkage analysis using the 40 pedigree CEPH reference panel and genotype data from these and other loci physically mapped to the terminal 1.5 Mb of chromosome 14q revealed an apparent increase in meiotic recombination within this region, relative to the average rate for the genome. Further, we found that recombination was higher in females than in males, indicating that the subtelomeric region of 14q differs from other human subtelomeric regions.

Chromosomes, Artificial, Yeast↗
PubMed2001

A statistical framework for quantitative trait mapping.

We describe a general statistical framework for the genetic analysis of quantitative trait data in inbred line crosses. Our main result is based on the observation that, by conditioning on the unobserved QTL genotypes, the problem can be split into two statistically independent and manageable parts. The first part involves only the relationship between the QTL and the phenotype. The second part involves only the location of the QTL in the genome. We developed a simple Monte Carlo algorithm to implement Bayesian QTL analysis. This algorithm simulates multiple versions of complete genotype information on a genomewide grid of locations using information in the marker genotype data. Weights are assigned to the simulated genotypes to capture information in the phenotype data. The weighted complete genotypes are used to approximate quantities needed for statistical inference of QTL locations and effect sizes. One advantage of this approach is that only the weights are recomputed as the analyst considers different candidate models. This device allows the analyst to focus on modeling and model comparisons. The proposed framework can accommodate multiple interacting QTL, nonnormal and multivariate phenotypes, covariates, missing genotype data, and genotyping errors in any type of inbred line cross. A software tool implementing this procedure is available. We demonstrate our approach to QTL analysis using data from a mouse backcross population that is segregating multiple interacting QTL associated with salt-induced hypertension.

Algorithms↗
PubMedDate not supplied

Finding consistent gene transmission patterns on large and complex pedigrees.

A heuristic algorithm for finding gene transmission patterns on large and complex pedigrees with partially observed genotype data is proposed. The method can be used to generate an initial point for a Markov chain Monte Carlo simulation or to check that the given pedigree and the genotype data are consistent. In small pedigrees, the algorithm is exact by exhaustively enumerating all possibilities, but, in large pedigrees, with a considerable amount of unknown data, only a subset of promising configurations can actually be checked. For that purpose, the configurations are ordered by combining the approximative conditional probability distribution of the unknown genotypes with the information on the relationships between individuals. We also introduce a way to divide the task into subparts, which has been shown to be useful in large pedigrees. The algorithm has been implemented in a program called APE (Allelic Path Explorer) and tested in three different settings with good results.

Algorithms↗
PubMed2005

How useful is the fine-scale mapping of complex trait linkage peaks? Evaluating the impact of additional microsatellite genotyping on the posterior probability of linkage.

The two-stage linkage mapping protocol for complex traits (a primary genome scan with low marker density followed by the high-density genotyping around linkage peaks) is a near-universal practice. The behavior (an increase or a decrease) of the peak upon such fine mapping frequently leads to inferences regarding the veracity of the primary scan finding, namely a true, or a false, positive. We examined by simulation, under the null hypothesis of no linkage and the alternative hypothesis of true linkage, the inferences that can be made regarding the posterior probability of linkage given either a peak increase, or alternatively, a peak decrease, following fine mapping. We considered different models of missing genotype data, fine-mapping LOD score thresholds, and prior probabilities of linkage. Our simulations show that evidence for linkage can increase frequently upon fine mapping under both null and alternative hypotheses, although large increases in LOD scores are more common under the alternative hypothesis. Increased LOD scores accompany an increased posterior probability of linkage, and large LOD score changes and the presence of dominance at the trait locus accentuate this effect. We demonstrate that the greatest changes in the posterior probability of linkage occur when the genotyping data are least complete (and especially when parental genotypes are missing), and the LOD score threshold for fine mapping is relaxed.

Algorithms↗
PubMed2004

Investigating the utility of combining phi29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArray genotyping.

BACKGROUND: Sustainable DNA resources and reliable high-throughput genotyping methods are required for large-scale, long-term genetic association studies. In the genetic dissection of common disease it is now recognised that thousands of samples and hundreds of thousands of markers, mostly single nucleotide polymorphisms (SNPs), will have to be analysed. In order to achieve these aims, both an ability to boost quantities of archived DNA and to genotype at low costs are highly desirable. We have investigated phi29 polymerase Multiple Displacement Amplification (MDA)-generated DNA product (MDA product), in combination with highly multiplexed BeadArray genotyping technology. As part of a large-scale BeadArray genotyping experiment we made a direct comparison of genotyping data generated from MDA product with that from genomic DNA (gDNA) templates. RESULTS: Eighty-six MDA product and the corresponding 86 gDNA samples were genotyped at 345 SNPs and a concordance rate of 98.8% was achieved. The BeadArray sample exclusion rate, blind to sample type, was 10.5% for MDA product compared to 5.8% for gDNA. CONCLUSIONS: We conclude that the BeadArray technology successfully produces high quality genotyping data from MDA product. The combination of these technologies improves the feasibility and efficiency of mapping common disease susceptibility genes despite limited stocks of gDNA samples.

Bacillus Phages↗
PubMed1993

Determination of relatedness between individuals using DNA fingerprinting.

Relatedness between individuals is an important element of genetic-epidemiological and evolutionary investigations in the context of anthropological research. In general, data on relationships between individuals are gathered from personal interviews or from examination of vital records. When blood samples are collected, such information can be validated from genotypic similarities of individuals. Although genotype data may offer opportunities to exclude certain types of relationships, inclusionary statements are necessarily only probabilistic in nature. The limitations of such probabilistic statements depend on the number of segregating alleles and the extent of polymorphisms at the loci employed. With the advent of DNA technology, several hypervariable single-locus probes (SLPs) and multilocus probes (MLPs) are now available for many organisms. These can be used to circumvent limitations of unequivocal assignment of relationships from genotype data. In this article we describe analytical principles for such investigations. In particular, we propose summary measures of DNA fingerprinting data (e.g., number of different alleles and number of shared alleles) that can be used to describe kinship relationships between individuals. We derive the expected distributions of number of alleles in individuals and of number of shared alleles between individuals of known relationships in a population. These distributions can be used in hypothesis testing to determine relatedness between individuals. We also derive the number of SLPs, each detecting a hypervariable polymorphism, needed to determine a specified relationship for given ranges of errors of prediction. Illustrations of the theory with data on several short tandem repeat loci and variable number of tandem repeat (VNTR) loci indicate that with 6 to 12 SLPs the parent-offspring pairs can be reliably distinguished from random pairs of individuals. This theory also serves the purpose of detecting inbreeding levels in a natural population.

Alleles↗
PubMed2000

Simple algorithm derived from a geno-/phenotypic database to predict HIV-1 protease inhibitor resistance.

BACKGROUND: Resistance against protease inhibitors (PI) can either be analysed genotypically or phenotypically. However, the interpretation of genotypic data is difficult, particularly for PI, because of the unknown contributions of several mutations to resistance and cross-resistance. OBJECTIVE: Development of an algorithm to predict PI phenotype from genotypic data. METHODS: Recombinant viruses containing patient-derived protease genes were analysed for sensitivity to indinavir, saquinavir, ritonavir and nelfinavir. Drug resistance-associated mutations were determined by direct sequencing. geno- and phenotypic data were compared for 119 samples from 97 HIV-1 infected patients. RESULTS: Samples with one or two mutations in the gene for the protease were phenotypically sensitive in 74.3%, whereas 83.6% of samples with five or more mutations were resistant against all PI tested. Some mutations (361, 63P, 71V/T, 771) were frequent both in sensitive and resistant samples, whereas others (241, 30N, 461/L, 48V, 54V, 82A/F/T/S, 84V, 90M) were predominantly present in resistant samples. Therefore, the presence or absence of a single drug resistance-associated mutation predicted phenotypic PI resistance with high sensitivity (96.5-100%) but low specificity (13.3-57.4%). A more specific algorithm was obtained by taking into account the total number of drug resistance-associated mutations in the gene for the protease and restricting these to certain key positions for the PI. The algorithm was subsequently validated by analysis of 72 independent samples. CONCLUSION: With an optimized algorithm, phenotypic PI resistance can be predicted by viral genotype with good sensitivity (89.1-93.0%) and specificity (82.6-93.3%). The reliability and relevance of this algorithm should be further evaluated in clinical practice.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Analysis of genetic variation in the GenomEUtwin project.

Multiallelic short tandem repeat polymorphisms, or microsatellites, are useful markers in genome wide scans to identify chromosomal regions containing genes underlying disease loci. The biallelic single nucleotide polymorphism (SNP) can be used to fine map previously identified large candidate regions or to test functional candidate genes by association analysis. In the GenomEUtwin project the population based impact of susceptibility genes for six multifactorial traits will be studied. A genome wide panel of informative human microsatellite markers will be analyzed by fluorescent capillary electrophoresis in well characterized twin and population samples. Contrary to microsatellites, selection of the most informative panels of SNPs is hampered by imperfect data on the allele frequencies and population distribution of SNPs markers in the databases. Therefore, selection of SNPs requires a substantial amount of bioinformatics, and, the SNPs need to be validated experimentally in the relevant populations prior to genotyping large sample sets. In the GenomEUtwin project, large scale genotyping of SNPs will be performed using the SNPstreamUHT and MassARRAY genotyping systems that are based on the primer extension reaction principle combined with fluorescent and mass spectrometric detection, respectively. Production of the genotyping data will be a joint effort by GenomEUtwin partners at the University of Helsinki, the National Public Health Institute in Helsinki, Finland and Uppsala University, Sweden. All genotyping data will be stored in a common database established specifically for the GenomEUtwin project, from where it can be accessed by the twin research centres that provided the samples for genotyping.

Databases, Genetic↗
PubMed2002

Association studies between microsatellite markers within the gene encoding human 11beta-hydroxysteroid dehydrogenase type 1 and body mass index, waist to hip ratio, and glucocorticoid metabolism.

Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert active cortisol (F) and inactive cortisone (E). 11beta-HSD1 is an oxo-reductase (E to F) expressed in several glucocorticoid target tissues, including liver and adipose tissue, where it facilitates glucocorticoid-induced gluconeogenesis and adipocyte differentiation, respectively. We have isolated a full-length HSD11B1 genomic clone; the gene is more than 30 kb in length, not 9 kb in length as previously reported, principally due to a large intron 4. Two polymorphic (CA)(n) repeats have been characterized within intron 4: a CA(19) repeat 2.7 kb 3' of exon 4 and a CA(15) repeat 3 kb 5' of exon 5. The microsatellites, CA(19) and CA(15), were PCR amplified using fluorescent primers and were genotyped on an ABI 377 DNA sequencer from DNA of 413 normal individuals enrolled in the MONICA study of cardiovascular risk factors and 557 Danish men (ADIGEN study), of whom 234 were obese [body mass index (BMI), >/=31 kg/m(2) ] at draft board examination and 323 were randomly selected controls from the draftee population with BMI below 31 kg/m(2) (mean +/- SE, 21.7 +/- 0.41). Genotypic data from the normal MONICA cohort was compared with gender, 5beta-tetrahydrocortisol+5alpha-tetrahydrocortisol/tetrahydrocortisone ratio, and waist to hip (W:H) ratio. When analyzed by allele length (0, 1, or 2 short alleles) for the CA(19) marker, there was a trend toward a higher 5beta-tetrahydrocortisol+5alpha-tetrahydrocortisol/tetrahydrocortisone ratio (P = 0.058) and an increased W:H ratio (2 vs. 0.1 short; P(c) = 0.10) with overrepresentation of short alleles. The opposite was true for the CA(15) locus, with longer alleles at this locus predicting increased 11beta-HSD1 activity, particularly in females. Genotypic data from the ADIGEN case-control population was compared with clinical markers of obesity such as BMI and W:H ratio. There was no significant difference in the distribution of either microsatellite marker between lean and obese groups. Allele distributions were binomial, as seen for the MONICA cohort, and the data were split accordingly (zero, one, or two short alleles). No significant association was seen between grouped alleles and the clinical parameters. No association was observed between HSD11B1 genotype and BMI in either population. These data suggest that 11beta-HSD1 is not a major factor in explaining genetic susceptibility to obesity per se. However, weak associations between HSD11B1 genotype, increased 11beta-HSD1 activity, and W:H ratio suggest that polymorphic variability at the HSD11B1 locus may influence susceptibility to central obesity through enhanced 11beta-HSD1 activity (E to F conversion) in visceral adipose tissue.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1995

[Hodgkin disease: recent histological and biological data].

Recent histologic, immunophenotypic and genotypic data have restricted the concept of Hodgkin's disease (HD) to the type 2 and 3 of Rye classification. This classification should be revised since the lymphocyte-predominance type has been shown to include the nodular paragranuloma which is a B-cell lymphoma, cases which have been confused with T-cell-rich large B-cell non Hodgkin's lymphoma (NHL) and cases which should be reclassified among the mixed cellularity group. Further more, most types 4 are now regarded as anaplastic large cell NHL. Immunophenotypic and genotypic studies support the heterogeneous nature of Reed-Sternberg and Hodgkin's (RSH) cells since they could be derived from B, T or null lymphocytes. In 50% of cases, RSH cells harbour the Epstein-Barr virus genome and express a viral protein, the latent membrane protein, which could play an oncogenic role in HD. Finally, RSH cells produce a wide range of cytokines that could stimulate their proliferation and explain the marked cellular reaction that is observed in HD.

Cytokines↗
PubMed2005

Alcoholism and related traits: a summary of Group 13 contributions.

Ten groups set out to study the genetics of alcoholism, using various measures of alcohol dependence such as Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, and related endophenotypes such as the electrophysiological evaluation of event-related potentials. The groups used both genome-wide microsatellite and single-nucleotide polymorphism (SNP) genotyping data in families selected from the Collaborative Study on the Genetics of Alcoholism. The majority of investigators studied alcohol-related phenotypes and chose linkage rather than association analysis. The analysis of SNP data presented several challenges, including marker linkage disequilibrium issues and computational limitations. Many groups pursued novel techniques, both in dealing with the SNP data and the definition of phenotypes. While there was a limited amount of concordance among linkage findings, it was very instructive to see so many new strategies at work. Generally the SNP genotype data seemed to yield more information for multipoint linkage analysis than the microsatellite data, a finding that will benefit the genetic analysis of complex disease in the future. A novel linkage peak was detected using the SNP markers.

Alcoholism↗
PubMed2006

A non-parametric approach to population structure inference using multilocus genotypes.

Inference of population structure from genetic markers is helpful in diverse situations, such as association and evolutionary studies. In this paper, we describe a two-stage strategy in inferring population structure using multilocus genotype data. In the first stage, we use dimension reduction methods such as singular value decomposition to reduce the dimension of the data, and in the second stage, we use clustering methods on the reduced data to identify population structure. The strategy has the ability to identify population structure and assign each individual to its corresponding subpopulation. The strategy does not depend on any population genetics assumptions (such as Hardy-Weinberg equilibrium and linkage equilibrium between loci within populations) and can be used with any genotype data. When applied to real and simulated data, the strategy is found to have similar or better performance compared with STRUCTURE, the most popular method in current use. Therefore, the proposed strategy provides a useful alternative to analyse population data.

Cluster Analysis↗
PubMed2001

Association between a single-nucleotide polymorphism in the promoter of the human interleukin-3 gene and rheumatoid arthritis in Japanese patients, and maximum-likelihood estimation of combinatorial effect that two genetic loci have on susceptibility to the disease.

Genetic variants of interleukin-3 (IL-3), a well-studied cytokine, may have a role in the pathophysiology of rheumatoid arthritis (RA); but reports on this association sometimes conflict. A case-control study was designed to investigate association between RA and a single-nucleotide polymorphism (SNP) in the IL-3 promoter region. Comparison of cases of RA versus control individuals yielded a chi(2) value of 14.28 (P=.0002), with a genotype odds ratio of 2.24 (95% confidence interval [95%CI] 1.44-3.49). When female cases with earlier onset were compared with female control individuals, the SNP revealed an even more significant correlation, with chi2=21.75 (P=.000004) and a genotype odds ratio of 7.27 (95%CI 2.80-18.89). The stronger association that we observed in this clinically distinct subgroup (females with early onset), within a region where linkage disequilibrium was not significantly extended, suggested that the genuine RA locus should locate either within or close to the IL-3 gene. Combined genotype data on SNPs on eight other candidate genes were combined with our IL-3 results, to estimate relationships between pairs of loci and RA, by maximum-likelihood analysis. The utility of combining the genotype data in this way to identify possible contributions of various genes to this disease is discussed.

Age of Onset↗
PubMed2005

Combining the meiosis Gibbs sampler with the random walk approach for linkage and association studies with a general complex pedigree and multimarker loci.

A linkage analysis for finding inheritance states and haplotype configurations is an essential process for linkage and association mapping. The linkage analysis is routinely based upon observed pedigree information and marker genotypes for individuals in the pedigree. It is not feasible for exact methods to use all such information for a large complex pedigree especially when there are many missing genotypic data. Proposed Markov chain Monte Carlo approaches such as a single-site Gibbs sampler or the meiosis Gibbs sampler are able to handle a complex pedigree with sparse genotypic data; however, they often have reducibility problems, causing biased estimates. We present a combined method, applying the random walk approach to the reducible sites in the meiosis sampler. Therefore, one can efficiently obtain reliable estimates such as identity-by-descent coefficients between individuals based on inheritance states or haplotype configurations, and a wider range of data can be used for mapping of quantitative trait loci within a reasonable time.

Computer Simulation↗
PubMed2005

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Bipolar Disorder↗
PubMed1991

Population genetics of hypervariable loci: analysis of PCR based VNTR polymorphism within a population.

Using a polymerase chain reaction (PCR) based method, genotypes at two hypervariable loci (3' to the Apo-B-structural gene and at the ApoC-II gene) were determined by size classification of alleles. Genotype data at the Apo-B locus (Apo-B VNTR) were obtained on 240 French Caucasians; the sample size for the ApoC-II VNTR was 162. For 160 individuals two-locus genotype data were available. Applications of some recently developed statistical methods to these data indicate that both of these loci are at Hardy-Weinberg equilibrium (HWE) and there is no indication of allelic associations between these two unlinked loci. In addition, the observed numbers of alleles (12 for the Apo-B and 11 for the ApoC-II VNTR loci) are also consistent with their respective expectations based on the observed heterozygosities (76.9% for the Apo-B and 85.9% for the ApoC-II loci) suggesting genetic homogeneity of this population-based sample. The multimodal distribution of allele sizes observed for both loci indicate that the production of new alleles at such VNTR loci may be caused by more than one molecular mechanism. The utility of such highly polymorphic loci for human genetic research and forensic applications are discussed in the context of these findings.

Alleles↗
PubMed1992

Linkage investigation of three putative tuberous sclerosis determining loci on chromosomes 9q, 11q, and 12q. The Tuberous Sclerosis Collaborative Group.

Previous linkage studies in tuberous sclerosis have implicated three disease determining loci at 9q, 11q, and 12q. We have collated phenotypic and genotypic data on 1622 members of 128 families with tuberous sclerosis in order to evaluate simultaneously the evidence for these putative loci. Affection status in the family members has been reassessed using uniform diagnostic criteria and genotypic data extensively checked before analysis under alternative models of locus heterogeneity. One tuberous sclerosis determining locus, accounting for approximately 50% of the families studied, has been found to map in the region of D9S10 on 9q34 but no evidence has been found to support the existence of major loci on 11q or 12q. A locus, or loci, elsewhere in the genome is likely to account for tuberous sclerosis in most non-chromosome 9 linked families.

Chromosome Mapping↗