1,368 research outputs found
Mapping a gene for rheumatoid arthritis on chromosome 18q21
No full textAlthough single chi-square analysis of the North American Rheumatoid Arthritis Consortium (NARAC) data identifies many single-nucleotide polymorphisms (SNPs) with p-values less than 0.05, none remain significant after Bonferroni correction. In contrast, CHROMSCAN evades heavy Bonferroni correction and auto-correlation between SNPs by using composite likelihood to model association across all markers in a region and permutation to assess significance. Analysis by CHROMSCAN identifies a 36-kb interval that includes the most significant SNP (msSNP) observed in a 10-Mb target suggested by linkage. Unexpectedly, stratification by gender and age of onset shows that association evidence comes almost entirely from females with age of onset less than 40. Combining evidence from a meta-analysis of linkage studies and three subsets of the NARAC data provides significant evidence for a determinant of rheumatoid arthritis in a 36-kb interval and illustrates the principle that estimates of location and its information are more powerful than estimates of p-values alone
Linkage disequilibrium maps and location databases
No full textEffective application of association mapping for complex traits requires characterization of linkage disequilibrium (LD) patterns that reflect the dominant process of recombination and its duration in addition to the more subtle influences of mutation, selection, and genetic drift. Maps expressed in linkage disequilibrium units (LDUs) reflect the influences of these factors with the use of a modified version of Malecot’s isolation-by-distance model. As a result, LDU maps are analogous to linkage maps in so far as their provision of an additive metric that is related to recombination and facilitates association-mapping studies. However, unlike linkage maps, LDUs also reflect the partly cumulative effects of multiple historical bottlenecks that account for substantial variations in LD patterns between populations. This chapter provides an overview of the data requirements and methodology used to construct LDU maps, their applications outside association mapping, and their integration into location databases
Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease
No full textMatrix metalloproteinase-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis, the pathology underlying the majority of coronary artery disease. We previously identified several polymorphisms in the gene encoding MMP-9. In this study we tested the hypothesis that variation in the matrix metalloproteinase-9 gene influences the development of atherosclerosis. Three common polymorphisms, i.e. m1562C>T, R+279Q and +6C>T, were analysed in 1510 white subjects undergoing coronary angiography. Analyses of individual polymorphisms showed that the frequencies of the C/T and T/T genotypes of the m1562C>T polymorphism were significantly higher in patients with coronary stenosis than in those with a normal angiogram. Logistic regression analyses indicated that individuals carrying the m1562T allele had an approx. 1.5-fold higher risk of developing coronary stenosis (OR 1.49, 95% CI 1.039-2.144), which was equivalent to an over 30% reduction in risk of coronary stenosis in individuals not carrying this allele (OR 0.670, 95% CI 0.467-0.963). The three polymorphisms studied were found to be in strong linkage disequilibrium. Haplotype analyses showed that the C-G-C haplotype (m1562C, +279Q and +6C) was associated with a protective effect against atherosclerosis. Individuals carrying this haplotype were at reduced risk of developing coronary stenosis (OR 0.695, 95% CI 0.530.92). Furthermore, the C-G-C haplotype was associated with less severe coronary atherosclerosis, i.e. carriers of this haplotype were at a lower risk of having coronary stenosis in more than one coronary artery (OR 0.796, 95% CI 0.640.99). These data, together with the previous finding that the m1562T allele has a higher transcriptional activity than the m1562C allele, support the notion that genetic variation with an effect on MMP-9 expression influences the development and progression of atherosclerosis
The influence of genetic variation in thirty selected genes on the clinical characteristics of early onset breast cancer
No full textIntroduction: common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.Methods: we selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association.Results: we confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease.Conclusions: we have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validatation by further studies in similar patient group
VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation
No full textFull author list omitted for brevity. For the full list of authors, see article.Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal
The Role of Mesointerpeduncular Circuitry in Anxiety
No full textAnxiety is an affective state defined by heightened arousal and unease in the absence of a clear and present fear-inducing stimulus. Chronic and inappropriate anxiety leads to anxiety disorders, the most common class of human mental disorder. Recent work suggests projections to the ventral tegmental area (VTA), are critical for anxiety behavior expression. However, the relationship between efferent VTA projections and anxiety is unclear. This thesis resolves anxiety circuitry connecting the dopaminergic (DAergic) VTA to the interpeduncular nucleus (IPN), coined the mesointerpeduncular circuit. I hypothesize the mesointerpeduncular circuit affects anxiety through the release of anxiogenic corticotropin releasing factor (CRF) during nicotine withdrawal and anxiolytic dopamine (DA) during drug naïve behavior. Electrophysiological and pharmacological data suggest CRF release from the DAergic VTA during nicotine withdrawal activates CRF receptor 1 (CRFR1) potentiating the glutamatergic activation of “Type 2” neurons and anxiety-like behavior in mice. However, in nicotine naïve conditions CRF production is negligible. Instead, in vivo DA release is anticorrelated with anxiety-like behaviors. Optogenetic stimulation and inhibition drives decreased and increased anxiety-like behaviors, respectively. Electrophysiological experiments reveal a complex interpeduncular microcircuit where D1-like DA receptor expressing “Type C” neurons in the caudal IPN (cIPN) regulate glutamatergic release in the ventral IPN (vIPN) through presynaptic GABA receptors. The result is propagation of the signal to excite “Type A” and inhibit “Type B” vIPN neurons. Finally, pharmacological activation or inhibition of interpeduncular D1-like DA receptors is sufficient to decrease and increase anxiety-like behaviors respectively. Thus, this circuit is important for modulating anxiety-like behavior.Neuroscienc
Properties of linkage disequilibrium (LD) maps
No full textA linkage disequilibrium map is expressed in linkage disequilibrium (LD) units (LDU) discriminating blocks of conserved LD that have additive distances and locations monotonic with physical (kb) and genetic (cM) maps. There is remarkable agreement between LDU steps and sites of meiotic recombination in the one body of data informative for crossing over, and good agreement with another method that defines blocks without assigning an LD location to each marker. The map may be constructed from haplotypes or diplotypes, and efficiency estimated from the empirical variance of LD is substantially greater for the metric based on evolutionary theory than for the absolute correlation r, and for the LD map compared with its physical counterpart. The empirical variance is nearly three times as great for the worst alternative (r and kb map) as for the most efficient approach (and LD map). According to the empirical variances, blocks are best defined by zero distance between included markers. Because block size is algorithm-dependent and highly variable, the number of markers required for positional cloning is minimized by uniform spacing on the LD map, which is estimated to have 1 LDU per locus, but with much variation among regions. No alternative representation of linkage disequilibrium (some of which are loosely called maps) has these properties, suggesting that LD maps are optimal for positional cloning of genes determining disease susceptibility
Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the alpha6 subunit
No full textCo-author Melissa Guildford Derner is a doctoral student in the Neuroscience Program in the Morningside Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.The prevalent co-abuse of nicotine and alcohol suggests a common neural mechanism underlying the actions of the two drugs. Nicotine, the addictive component of tobacco, activates nicotinic acetylcholine receptors (nAChRs) containing the alpha6 subunit (alpha6* nAChRs) in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA), a region known to be crucial for drug reward. Recent evidence suggests that ethanol may potentiate ACh activation of these receptors as well, although whether alpha6* nAChR expression is necessary for behavioral effects of acute ethanol exposure is unknown. We compared binge-like ethanol consumption and ethanol reward sensitivity between knockout (KO) mice that do not express chrna6 (the gene encoding the alpha6 nAChR subunit, the alpha6 KO line) and wild-type (WT) littermates using the Drinking-in-the-Dark (DID) and Conditioned Place Preference (CPP) assay, respectively. In the DID assay, alpha6 KO female and male mice consumed ethanol similarly to WT mice at all concentrations tested. In the CPP assay, 2.0-g/kg and 3.0-g/kg, but not 0.5-mg/kg, ethanol conditioned a place preference in WT female and male mice, whereas only 2.0-g/kg ethanol conditioned a place preference in alpha6 KO mice. Acute challenge with ethanol reduced locomotor activity, an effect that developed tolerance with repeated injections, similarly between genotypes in both female and male mice. Together, these data indicate that expression of alpha6* nAChRs is not required for binge-like ethanol consumption and reward, but modulate sensitivity to the rewarding properties of the drug.Neuroscienc
Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps
No full textGenetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences
Whole genome sequences are required to fully resolve the linkage disequilibrium structure of human populations
No full textBACKGROUND: An understanding of linkage disequilibrium (LD) structures in the human genome underpins much of medical genetics and provides a basis for disease gene mapping and investigating biological mechanisms such as recombination and selection. Whole genome sequencing (WGS) provides the opportunity to determine LD structures at maximal resolution.RESULTS: We compare LD maps constructed from WGS data with LD maps produced from the array-based HapMap dataset, for representative European and African populations. WGS provides up to 5.7-fold greater SNP density than array-based data and achieves much greater resolution of LD structure, allowing for identification of up to 2.8-fold more regions of intense recombination. The absence of ascertainment bias in variant genotyping improves the population representativeness of the WGS maps, and highlights the extent of uncaptured variation using array genotyping methodologies. The complete capture of LD patterns using WGS allows for higher genome-wide association study (GWAS) power compared to array-based GWAS, with WGS also allowing for the analysis of rare variation. The impact of marker ascertainment issues in arrays has been greatest for Sub-Saharan African populations where larger sample sizes and substantially higher marker densities are required to fully resolve the LD structure.CONCLUSIONS: WGS provides the best possible resource for LD mapping due to the maximal marker density and lack of ascertainment bias. WGS LD maps provide a rich resource for medical and population genetics studies. The increasing availability of WGS data for large populations will allow for improved research utilising LD, such as GWAS and recombination biology studies.<br/
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