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At least 163 records · Page 9Linked to original sources
PubMed1997

Genome screening using extremely discordant and extremely concordant sib pairs.

We applied extreme sib-pair methods in two ways to the GAW10 Problem 2A data sets to detect susceptible quantitative trait loci using extremely discordant sib pairs only, and combining them with the available extremely concordant sib pairs as suggested by the authors elsewhere. Ten successive original replicates were combined into one sampling pool so as to get the necessary number of extreme sib pairs. A total of 100 replicates were used to produce 10 such data sets for both initial detection and confirmations. Strong signals were found with markers D5G15 for Q1, D8G27-28 for Q4, and D9G7-9 for Q5.

Chromosome Mapping↗
PubMed2004

Genomic screen for loci associated with alcohol dependence in Mission Indians.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain elusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians.

Adolescent↗
PubMed1999

Genome screen and candidate gene studies in parasitized populations.

The immunoglobulin E (IgE) antibody system is important in the genesis of asthma, but it appears to have originally evolved for defence against parasite infection. In order to study how IgE contributes to asthma, there are advantages in studying parasitized populations. Firstly, the IgE system can be studied when it is operating in a more natural state, and this could allow new insight into basic immune function. Secondly, the genetic susceptibility to produce high levels of IgE is more likely to be expressed, as the most intense IgE responses in nature are those found in the presence of parasitic infection. These more intense IgE responses should facilitate finding new 'asthma genes', assist in investigating how the DNA variations in candidate genes affect gene function and provide the possibility of developing new approaches to the treatment of asthma.

Asthma↗
PubMed2005

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Age of Onset↗
PubMed2000

Combined linkage and linkage disequilibrium mapping for genome screens.

Linkage analysis and association studies, two major approaches for genetic studies of human diseases, are useful for mapping genes that are highly penetrant, but both use only part of the information that is available for mapping disease genes. Therefore, they provide limited utility when used alone. In this report, we present combined linkage and linkage disequilibrium mapping that simultaneously utilizes linkage and linkage disequilibrium information for mapping human disease genes. Compared with the existing linkage analysis and association study methods, this method has several advantages: 1) it has high statistical power by a joint analysis of linkage and linkage disequilibrium for localizing disease susceptibility loci: 2) it unifies the theory of linkage analysis and linkage disequilibrium mapping, 3) it retains the general framework for linkage analysis and, hence, can be easily incorporated into the existing software for the linkage analysis. The proposed LLDM is applied to familial hemophagocytic lymphohistiocytosis (FHL) disease.

Chromosome Mapping↗
PubMed2001

Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci.

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.

Chromosome Mapping↗
PubMed2007

Interpretation of simultaneous linkage and family-based association tests in genome screens.

Linkage and association analyses have played important roles in identifying susceptibility genes for complex diseases. Linkage tests and family-based tests of association are often applied in the same data to help fine-map disease loci or validate results. This paradigm increases efficiency by making maximal use of family data sets. However, it is not intuitively clear under what conditions association and linkage tests performed in the same data set may be correlated. Understanding this relationship is important for interpreting the combined results of both tests. We used computer simulations and theoretical statements to estimate the correlation between linkage statistics (affected sib pair maximum LOD scores) and family-based association statistics (pedigree disequilibrium test (PDT) and association in the pressure of linkage (APL)) under various hypotheses. Different types of pedigrees were studied: nuclear families with affected sib pairs, extended pedigrees and incomplete pedigrees. Both simulation and theoretical results showed that when there is no linkage or no association, the linkage and association tests are not correlated. When there is linkage and association in the data, the two tests have a positive correlation. We concluded that when linkage and association tests are applied in the same data, the type I error rate of neither test will be affected and that power can be increased by applying tests conditionally.

Alleles↗
PubMed2003

A functional genomic screen for cardiogenic genes using RNA interference in developing Drosophila embryos.

Identifying genetic components is an essential step toward understanding complex developmental processes. The primitive heart of the fruit fly, the dorsal vessel, which is a hemolymph-pumping organ, has provided a unique model system to identify cardiogenic genes and to further our understanding of the molecular mechanisms of cardiogenesis. Using RNA interference in developing Drosophila embryos, we performed a genomewide search for cardiogenic genes. Through analyses of the >5800 genes that cover approximately 40% of all predicted Drosophila genes, we identified a variety of genes encoding transcription factors and cell signaling proteins required for different steps during heart development. Analysis of mutant heart phenotypes and identified genes suggests that the Drosophila heart tube is segmentally patterned, like axial patterning, but assembled with regional modules. One of the identified genes, simjang, was further characterized. In the simjang mutant embryo, we found that within each segment a subset of cardial cells is missing. Interestingly, the simjang gene encodes a protein that is a component of the chromatin remodeling complex recruited by methyl-CpG-DNA binding proteins, suggesting that epigenetic information is crucial for specifying cardiac precursors. Together, these studies not only identify key regulators but also reveal mechanisms underlying heart development.

Animals↗
PubMed2005

A genomic screen for yeast vacuolar membrane ATPase mutants.

V-ATPases acidify multiple organelles, and yeast mutants lacking V-ATPase activity exhibit a distinctive set of growth defects. To better understand the requirements for organelle acidification and the basis of these growth phenotypes, approximately 4700 yeast deletion mutants were screened for growth defects at pH 7.5 in 60 mm CaCl(2). In addition to 13 of 16 mutants lacking known V-ATPase subunits or assembly factors, 50 additional mutants were identified. Sixteen of these also grew poorly in nonfermentable carbon sources, like the known V-ATPase mutants, and were analyzed further. The cwh36Delta mutant exhibited the strongest phenotype; this mutation proved to disrupt a previously uncharacterized V-ATPase subunit. A small subset of the mutations implicated in vacuolar protein sorting, vps34Delta, vps15Delta, vps45Delta, and vps16Delta, caused both Vma- growth phenotypes and lower V-ATPase activity in isolated vacuoles, as did the shp1Delta mutation, implicated in both protein sorting and regulation of the Glc7p protein phosphatase. These proteins may regulate V-ATPase targeting and/or activity. Eight mutants showed a Vma- growth phenotype but no apparent defect in vacuolar acidification. Like V-ATPase-deficient mutants, most of these mutants rely on calcineurin for growth, particularly at high pH. A requirement for constitutive calcineurin activation may be the predominant physiological basis of the Vma- growth phenotype.

Adenosine Triphosphatases↗
PubMed2003

A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study.

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.

Adult↗
PubMed2005

A sex-adjusted and age-adjusted genome screen for nested alcohol dependence diagnoses.

Alcohol dependence is a complex disorder with a substantial genetic contribution to susceptibility. The Collaborative Study on the Genetics of Alcoholism is a multi-site study whose purpose is to detect, localize, and characterize genes contributing to this susceptibility. Previous linkage analyses of the trait of alcohol dependence in Collaborative Study on the Genetics of Alcoholism have used affected sib-pair methods with a dichotomous phenotype definition. In contrast, the analysis in this paper uses a sex-adjusted and age-adjusted multiple threshold liability model. The use of such a model, in that it includes unaffected as well as as affected subjects and in that it utilizes the differential severity of a diagnosis scale, should heuristically be more powerful than a straight affected sib-pair analysis. Three regions of interest are found on chromosome 1 (lod 5.17), chromosome 4 (lod 3.46), and chromosome 8 (lod 4.31). The region on chromosome 1 near the marker D1S532 is in the region previously reported as linked to alcohol dependence and correlated phenotypes in this dataset. The region on chromosome 4 near the alcohol dehydrogenase gene cluster has been reported to be linked to alcohol dependence in other studies, as well as to the alcohol consumption phenotype 'Maximum Number of Drinks in a 24-Hour Period' in this dataset. The region on chromosome 8 near the marker D8S1988 is homologous to a section of rat chromosome 5 to which an alcohol consumption phenotype has been linked.

Alcohol Drinking↗
PubMed2004

Genome screen for a combined bone phenotype using principal component analysis: the Framingham study.

Genetic factors substantially contribute to variation in bone mass. There is a controversy as to whether shared genetic factors exist for bone mass at different sites. We hypothesize that using a composite phenotypic score of several correlated bone mass measures may provide complementary results for linkage studies. In the members of 323 pedigrees from the Framingham Osteoporosis Study, bone mineral density (BMD) was measured at the lumbar spine and three femoral sites (Lunar DPX-L), and quantitative ultrasound (QUS) measured at the calcaneus (Hologic Sahara). Data on age, sex, anthropometry, alcohol and caffeine intake, smoking status, physical activity, menopause, and estrogen use (in females) were also obtained. Principal component analyses of BMD and QUS phenotypes were performed in each sex and generation (parents and offspring). The principal component analyses yielded two components, whose loadings were extracted as principal component scores (PC1 and PC2) for each individual, with PC1 explaining up to 66% of the total variation of all bone mass measurements, and PC2 an additional 24%. Principal component analysis of the three femoral BMD measures resulted in one component (PC_hip) that explained 89-91% of the common variation of hip BMD measures. Quantitative genetic analysis (using the variance components method) revealed that both principal component scores were under significant genetic influences (covariate-adjusted heritabilities of PC1, PC2, and PC_hip were 0.66 +/- 0.07, 0.44 +/- 0.07, and 0.61 +/- 0.06, respectively). For PC1, loci of suggestive linkage were identified on chromosomes 1q21.3 and 8q24.3 with the maximum multipoint LOD scores 2.5 and 2.4, respectively. For PC2, multipoint LOD score was 2.1 on 1p36. Suggestive linkage of PC_hip was found on 8q24.3 and 16p13.2 (LODs>1.9). In conclusion, an approach to linkage analysis using the linear combination of several correlated bone phenotypes suggests that there are chromosomal loci regulating bone mass, with seemingly pleiotropic effects at different skeletal sites.

Adult↗
PubMed2006

Genomic screening in vivo reveals the role played by vacuolar H+ ATPase and cytosolic acidification in sensitivity to DNA-damaging agents such as cisplatin.

Screening the Saccharomyces cerevisiae homozygous diploid deletion library against a sublethal concentration of cisplatin revealed 76 strains sensitive to the drug. As expected, the largest category of deletions, representing 40% of the sensitive strains, was composed of strains lacking genes involved in DNA replication and damage repair. Deletions lacking function of the highly conserved vacuolar H+ translocating ATPase (V-ATPase) composed the category representing the second largest number of sensitive strains. The effect on cell death exhibited by V-ATPase mutants was found to be a general response to various DNA damaging agents as opposed to being specific to cisplatin, as evidenced by sensitivity of the mutants to hydroxyurea (a DNA-alkylating agent) and UV irradiation. Loss of V-ATPase does not affect DNA repair, because double mutants defective for V-ATPase function and DNA repair pathways were more sensitive to cisplatin than the single mutants. V-ATPase mutants are more prone to DNA damage than wild-type cells, indicated by enhanced activation of the DNA damage checkpoint. Vacuole function per se is not cisplatin-sensitive, because vacuolar morphology and vacuolar acidification were unaffected by cisplatin in wild-type cells. V-ATPase also controls cytoplasmic pH, so the enhanced sensitivity to DNA damage may be associated with the drop in pHi associated with V-ATPase mutants. The increased loss in cell viability induced by cisplatin at lower pH in V-ATPase mutants supports this hypothesis. The loss in viability seen in wild-type cells under the same conditions was far less dramatic.

Antineoplastic Agents, Alkylating↗
PubMed1999

Genome screen for platelet monoamine oxidase (MAO) activity.

To identify loci involved in the control of platelet monoamine oxidase B (MAO-B) activity, a genomewide linkage screen was performed using 291 markers in 148 nuclear families containing a total of 1,008 nonindependent sib-pairs. Participants were genotyped and their platelet MAO-B activity levels were measured as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Sib-pair analysis using Haseman-Elston regression was carried out with two programs. Two-point analysis on all pairs with SIBPAL indicated three markers with p-values below 0.01: D6S1018 (p = 0.0004), D2S1328 (p = 0.008), and D2S408 (p = 0.003). MAPMAKER/SIBS multipoint analyses using independent pairs(N = 409) gave maximal lod scores of 2. 0 on chromosome 6 and 1.1 and 1.4 for the two regions on chromosome 2. These results are consistent with linkage, but do not provide definitive evidence. We are currently creating a denser map in these regions and have begun genotyping a second sample in COGA.

Blood Platelets↗
PubMed2003

Genomic screen for genes involved in mammalian craniofacial development.

Using a subtractive hybridisation approach, we enriched for genes likely to play a role in embryonic development of the mammalian face and other structures. This was achieved by subtracting cDNA derived from adult mouse liver from that derived from 10.5 dpc mouse embryonic branchial arches 1 and 2. Random sequencing of clones from the resultant library revealed that a high percentage correspond to genes with a previously established role in embryonic development and disease, while 15% represent novel or uncharacterised genes. Whole mount in situ hybridisation analysis of novel genes revealed that approximately 50% have restricted expression during embryonic development. In addition to expression in branchial arches, these genes showed a range of expression domains commonly including neural tube and somites. Notably, all genes analysed were found to be expressed not only in the branchial arches but also in the developing limb buds, providing support for the hypothesis that development of the limbs and face is likely to involve analogous molecular processes.

Animals↗
PubMed2002

Characteristics of genetic markers and maps for cost-effective genome screens using diallelic markers.

New technologies for genotyping diallelic markers (SNPs) were recently developed that may be lower in cost, and more easily automated than microsatellite markers (STRPs). The reduction in genotyping costs resulting from such automation may significantly impact the overall cost of studies of complex traits, which generally require large sample sizes. Use of multiple SNPs in linkage analysis can recapture the linkage information otherwise lost with such markers. Here we derive a measure of the multilocus polymorphic information content (MPIC) in the context of linkage analysis for a cluster of SNPs, and we explore the characteristics of uniform vs. clustered SNP maps, relative to STRP maps. Issues addressed in comparing the map structures include the information content for clustered or single markers, and map accuracy. To be cost-effective, SNPs should have a common allele frequency between 0.5-0.75. No more than five loci per cluster are needed. Some linkage disequilibrium between loci in a cluster is tolerable. In the ideal case, a uniformly spaced SNP map is more cost-effective than one composed of clustered loci. However, the genotyping cost per marker for diallelic markers can be at most 60% of the genotyping cost per marker for STRPs. The consequences of using clustered vs. uniform SNP maps are considered in the context of map inaccuracy and use of multipoint vs. pairwise linkage analysis. Overall, when marker information, map accuracy, and flexibility of analysis are jointly considered, an optimal solution may be use of maps with 2-3 SNPs per cluster.

Alleles↗
PubMed2003

A score for Bayesian genome screening.

Bayesian Monte Carlo Markov chain (MCMC) techniques have shown promise in dissecting complex genetic traits. The methods introduced by Heath ([1997], Am. J. Hum. Genet. 61:748-760), and implemented in the program Loki, have been able to localize genes for complex traits in both real and simulated data sets. Loki estimates the posterior probability of quantitative trait loci (QTL) at locations on a chromosome in an iterative MCMC process. Unfortunately, interpretation of the results and assessment of their significance have been difficult. Here, we introduce a score, the log of the posterior placement probability ratio (LOP), for assessing oligogenic QTL detection and localization. The LOP is the log of the posterior probability of linkage to the real chromosome divided by the posterior probability of linkage to an unlinked pseudochromosome, with marker informativeness similar to the marker data on the real chromosome. Since the LOP cannot be calculated exactly, we estimate it in simultaneous MCMC on both real and pseudochromosomes. We investigate empirically the distributional properties of the LOP in the presence and absence of trait genes. The LOP is not subject to trait model misspecification in the way a lod score may be, and we show that the LOP can detect linkage for loci of small effect when the lod score cannot. We show how, in the absence of linkage, an empirical distribution of the LOP may be estimated by simulation and used to provide an assessment of linkage detection significance.

Bayes Theorem↗