The specific aims of the project (Z01 HG000200) are: 1) to develop methods of genetic analysis that address statistical problems involving the detection of trait loci and new marker technologies (e.g., SNPs); 2) to use computer simulation to investigate the statistical properties of existing and newly developed methods for the genetic analysis of quantitative traits, and to apply insights gained from these simulations to ongoing collaborative studies, 3) to identify genetic effects underlying quantitative traits using statistical genetic analysis in collaborative family studies; and 4) to continue the development and dissemination of the Genometric Analysis Simulation Package (G.A.S.P.).? ? Theoretical work during the past year continued to focus on the revision of linear regression based tests of associations for quantitative traits and alternatives to theoretically based determination of type I error rates. The linear model for the Regression of Offspring on Mid-Parent (ROMP) method is a hybrid of the traditional regression of offspring on mid-parent model used to estimate heritability and the ANOVA model used to test for association. A revised version of the regression of Offspring on Mid-Parent method, ROMPrev, was developed within the context of collapsibility in linear regression models in order to determine the standard error of the difference between two regressions [Roy-Gagnon et al, submitted]. This method was applied to electroencephalogram phenotype data from the COGA dataset [Roy-Gagnon et al. 2005]. ROMP has also been extended to include missing values and applications to haplotypes.? ? With respect to developing alternatives to theoretically based determination of type I error rates, an empiric method, the Applied Pseudo-Trait (APT) method, was applied to data from the Framingham Heart Study. Rather than relying on a series of assumptions that may or may not be met in the underlying data, APT uses the actual locations, number of alleles and allelic frequencies of the actual marker data, the distribution of recombination, the family structures present in the data, and any genotyping errors that may be present in the data. The method is similar in spirit to the simulation and permutation methods, but it does not require computer simulation or many repetitions of the genomic screen [Papanicolaou et al. 2005].? ? In addition, a graphical method for the presentation of p-values from sliding window haplotype tests of association was developed [Mathias et al. 2006]. This method provides a convenient and easy to interpret graph that identifies the strength and width of p-values that exceed specified critical values with a sliding window approach. This approach can be used to help to identify and narrow candidate regions for any ?moving average? type test, not just for test of association. A software tool, Graphical Assessment of Sliding P-values (GrASP), was developed to simplify the presentation and visualization of results in these types of analyses. The software was developed in collaboration with the JHU Center for Inherited Disease Research (CIDR).? ? With genotyping for several project completed during 2005, most of the effort during the past year focused on statistical genetic analysis in collaborative studies.? ? Familial idiopathic scoliosis. Four manuscripts from the scoliosis projects were published since the last annual report. The most significant of these publications was the results of the linkage and association analyses of scoliosis and short tandem repeat polymorphic (STRP) marker genomic screen from a sample of 1200 individuals in 202 families with at least two individuals with scoliosis. In this study, primary candidate regions were identified on chromosomes 6, 9, 16 and 17 [Miller et al. 2005]. In a second study, a subset of the original sample was selected based on the presence of kyphoscoliosis [Miller et al., 2006]. Candidate regions on chromosomes 5p13 and 13q13-32 were identified, and three members of the Iroquois homeobox gene family, (IRX1, IRX2 and IRX4), were virtually the only genes located in the candidate region of chromosome 5. Somewhat surprisingly, all the other genes in the IRX homeobox gene family are located in the candidate region on chromosome 13; this finding makes the IRX gene family loci particularly attractive. Single nucleotide polymorphic (SNP) markers are being genotyped in several of these candidate regions in an attempt to narrow the regions identified with linkage analysis and to identify specific allelic variants that may be responsible for susceptibility to the development of scoliosis and variation in the degree of lateral curvature.? ? Work continues on the genetic analysis of a STRP screen in a replication sample of families with familial idiopathic scoliosis that has characteristics nearly identical to those of the sample analyzed in Miller et al. [2005]. Preliminary analyses suggests that of the 11 regions identified in the original study, at least 7 of these regions can be considered to be true replications [Behnemann et al. in preparation]. The replication of the original candidate regions is another critical step in identifying candidate loci in subsequent association studies. ? ? Other publications from the scoliosis project included a failure to replicate a previously reported association between familial idiopathic scoliosis and markers in the aggrecan locus [Marosy et al., 2006] and replication of a candidate region on chromosome 19p13 [Alden et al., 2006] that was previously reported in a sample of families in China.? ? Genetic analysis of drug treatment response in the Sequenced Treatment Alternatives for Depression (STAR*D). As part of collaborations with investigators from NIMH and the Southwestern Medical Center (John Rush), candidate loci that may be responsible, at least in part, for response to selective serotonin reuptake inhibitors (SSRIs) were identified and SNPs within each candidate locus were genotyped with the Illumina platform. Several manuscripts have been submitted or are in preparation.? In the most significant publication to date, non-parametric tests for association of remitter status and responder status for citalopram with each of 768 SNPs were performed on initial and replication samples of available cases. One SNP was highly significant in both the test and replication sample. This SNP is located in the serotonin 2A receptor (5HT2A).? ? Hypertension. Two manuscripts have been published as part of collaborations with Drs. Audrey Choh and Roger Siervogel of Wright State University Medical Center. These studies are part of a long-term collaboration between Drs. Siervogel and Wilson. The studies focus on genetic analysis of blood pressure response to different stressors, in the first case the stressor is the cold pressor test [Choh et al. 2005], in the second case the stressor is orthostatic tilt [Choh et al. 2006]. ? ? Genetics of type II diabetes in India. Progress continues on the recruitment of families in Indiaa. The goal of the project is to recruit 30 large multiplex families to study the genetics of type II diabetes in an Indian population. Approximately 18 families have been recruited at this point. DIR funds were used to continue a contract with collaborators at the Madras Diabetes Research Foundation for family recruitment, and statistical analysis for tests of association of SNPs in candidate genes were performed.
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