Objective Quantitative trait loci identified in animal models provide potential candidate

Objective Quantitative trait loci identified in animal models provide potential candidate susceptibility loci for human disorders. unlikely to be the functional variants themselves, we constructed haplotype blocks using the default confidence interval procedure in Haploview 3.2 to better understand the LD structure around these markers. Markers 10, 11, and 12 occurred on a single haplotype block in our sample, although the LD between these and marker 9 was high, consistent with CEU HapMap data, suggesting one large block structure across the SNPs in this region. We therefore tested the association of Rabbit Polyclonal to LFA3. the four-marker haplotypes created from combinations of markers 9C12. In Table 2, we present the results, by stage, for these four-marker haplotypes as calculated using UNPHASED (results for three-marker and five-marker sliding window haplotypes produced similar patterns). As indicated, the most consistent result across stages is for the common protective C-T-G-G haplotype, showing higher frequencies in controls than cases (= 0.0036 in the combined sample). The less common T-T-A-A haplotype showed a nominal association with an increased risk (= 0.029). As we are testing five markers in both stages (or five haplotypes derived from four of these markers), we applied a corrected = 0.0036) occurs less than 5% of the time by chance. Table 2 Haplotype analysis results for RGS1 block single-nucleotide polymorphisms in stage 1, stage 2, and the combined samplesa Discussion In this study, we examined whether human genes syntenic to the Calcipotriol murine chromosome 1 emotionality region were associated with genetic susceptibility to human internalizing phenotypes, including anxiety disorders, major depression, and Calcipotriol neuroticism. This susceptibility was indexed by a latent genetic factor common to these phenotypes derived from multivariate twin modeling. We entered the resulting sample of 589 high genetic risk and Calcipotriol 539 low genetic Calcipotriol risk individuals into a two-stage association study in which markers from the candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Individual markers and relevant haplotypes were analyzed. Out of the 31 markers tested in this region, five in and around the gene fulfilled the threshold screening criterion in stage 1 of is a Calcipotriol small gene (4.3 kb) that codes for one of the many members of the class of proteins known as regulators of G-protein signaling. These proteins attenuate the signaling activity of G-proteins by binding to activated, GTP-bound Ga subunits and increase the rate of conversion of GTP into GDP. As summarized on the UCSC Genome Browser website (www.genome.ucsc.edu), has little known brain expression, limited to the hypothalamus and the corpus callosum. Extant research supports its role in B-cell inflammatory responses (Moratz (2008) identified human SNPs corresponding to functional and conserved regions in the murine emotionality locus and tested them for association in a large, extreme-selected sample for neuroticism. They reported a significant association for SNP rs6428058, about 600 kb upstream of (outside of our selected region). They did not genotype any markers overlapping the block implicated in the current study. We note that neither that study nor the current one found evidence supporting a role for the gene in internalizing disorder susceptibility. The results of this study should be interpreted in the context of several potential limitations. First, this sample, although chosen to maximize power to directly test an association with a common genetic risk for internalizing phenotypes and selected from the informative tails of a much larger sample, may nonetheless lack sufficient power to detect an association with common genetic polymorphisms that have modest effect sizes. In particular, although we attempted to balance type I and type II errors and maintain an available sample for replication using a two-stage study design with less stringent stage 1 screening gene and internalizing disorders. As with any novel genetic association finding, these results should be considered as tentative until adequate replication is shown. Acknowledgements The authors thank Drs Jonathan Flint and Saffron Willis-Owen for useful discussions on their chromosome 1 association data (Fullerton et al., 2008). This work was supported by NIH grants MH-40828, MH-65322, MH-20030, DA-11287, MH/AA/DA-49492 (K.S.K.), and NIH grant K08 MH-66277, a NARSAD Young.

Leave a Reply

Your email address will not be published.

Proudly powered by WordPress
Theme: Esquire by Matthew Buchanan.