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1.  Identifying rare variants from exome scans: the GAW17 experience 
BMC Proceedings  2011;5(Suppl 9):S1.
Genetic Analysis Workshop 17 (GAW17) provided a platform for evaluating existing statistical genetic methods and for developing novel methods to analyze rare variants that modulate complex traits. In this article, we present an overview of the 1000 Genomes Project exome data and simulated phenotype data that were distributed to GAW17 participants for analyses, the different issues addressed by the participants, and the process of preparation of manuscripts resulting from the discussions during the workshop.
doi:10.1186/1753-6561-5-S9-S1
PMCID: PMC3287821  PMID: 22373325
2.  Power and false-positive rates for the restricted partition method (RPM) in a large candidate gene data set 
BMC Proceedings  2009;3(Suppl 7):S74.
Many phenotypes of public health importance (e.g., diabetes, coronary artery disease, major depression, obesity, and addictions to alcohol and nicotine) involve complex pathways of action. Interactions between genetic variants or between genetic variants and environmental factors likely play important roles in the functioning of these pathways. Unfortunately, complex interacting systems are likely to have important interacting factors that may not readily reveal themselves to univariate analyses. Instead, detecting the role of some of these factors may require analyses that are sensitive to interaction effects.
In this study, we evaluate the sensitivity and specificity of the restricted partition method (RPM) to detect signals related to coronary artery disease in the Genetic Analysis Workshop 16 Problem 3 data using the 50,000 k candidate gene single-nucleotide polymorphism set. Power and false-positive rates were evaluated using the first 100 replicate datasets. This included an exploration of the utility of using of all genotyped family members compared with selecting one member per family.
PMCID: PMC2795976  PMID: 20018069
3.  The Genetic Analysis Workshop 16 Problem 3: simulation of heritable longitudinal cardiovascular phenotypes based on actual genome-wide single-nucleotide polymorphisms in the Framingham Heart Study 
BMC Proceedings  2009;3(Suppl 7):S4.
The Genetic Analysis Workshop (GAW) 16 Problem 3 comprises simulated phenotypes emulating the lipid domain and its contribution to cardiovascular disease risk. For each replication there were 6,476 subjects in families from the Framingham Heart Study (FHS), with their actual genotypes for Affymetrix 550 k single-nucleotide polymorphisms (SNPs) and simulated phenotypes. Phenotypes are simulated at three visits, 10 years apart. There are up to 6 "major" genes influencing variation in high- and low-density lipoprotein cholesterol (HDL, LDL), and triglycerides (TG), and 1,000 "polygenes" simulated for each trait. Some polygenes have pleiotropic effects. The locus-specific heritabilities of the major genes range from 0.1 to 1.0%, under additive, dominant, or overdominant modes of inheritance. The locus-specific effects of the polygenes ranged from 0.002 to 0.15%, with effect sizes selected from negative exponential distributions. All polygenes act independently and have additive effects. Individuals in the LDL upper tail were designated medicated. Subjects medicated increased across visits at 2%, 5%, and 15%. Coronary artery calcification (CAC) was simulated using age, lipid levels, and CAC-specific polymorphisms. The risk of myocardial infarction before each visit was determined by CAC and its interactions with smoking and two genetic loci. Smoking was simulated to be commensurate with rates reported by the Centers for Disease Control. Two hundred replications were simulated.
PMCID: PMC2795938  PMID: 20018031
4.  A search for non-chromosome 6 susceptibility loci contributing to rheumatoid arthritis 
BMC Proceedings  2009;3(Suppl 7):S15.
We conducted a search for non-chromosome 6 genes that may increase risk for rheumatoid arthritis (RA). Our approach was to retrospectively ascertain three "extreme" subsamples from the North American Rheumatoid Arthritis Consortium. The three subsamples are: 1) RA cases who have two low-risk HLA-DRB1 alleles (N = 18), 2) RA cases who have two high-risk HLA-DRB1 alleles (N = 163), and 3) controls who have two low-risk HLA-DRB1 alleles (N = 652). We hypothesized that since Group 1's RA was likely due to non-HLA related risk factors, and because Group 3, by definition, is unaffected, comparing Group 1 with Group 2 and Group 1 with Group 3 would result in the identification of candidate susceptibility loci located outside of the MHC region. Accordingly, we restricted our search to the 21 non-chromosome 6 autosomes. The case-case comparison of Groups 1 and 2 resulted in the identification of 17 SNPs with allele frequencies that differed at p < 0.0001. The case-control comparison of Groups 1 and 3 identified 23 SNPs that differed in allele frequency at p < 0.0001. Eight of these SNPs (rs10498105, rs2398966, rs7664880, rs7447161, rs2793471, rs2611279, rs7967594, and rs742605) were common to both lists.
PMCID: PMC2795911  PMID: 20018004
5.  Detecting population stratification using related individuals 
BMC Proceedings  2009;3(Suppl 7):S106.
Although identification of cryptic population stratification is necessary for case/control association analyses, it is also vital for linkage analyses and family-based association tests when founder genotypes are missing. However, including related individuals in an analysis such as EIGENSTRAT can result in bias; using only founders or one individual per pedigree results in loss of data and inaccurate estimates of stratification. We examine a generalization of principal-component analyses to allow for the inclusion of related individuals by down-weighting the significance of individual comparisons.
PMCID: PMC2795877  PMID: 20017970
6.  Linkage, case-control association, and family-based association tests for complex disorders 
BMC Proceedings  2007;1(Suppl 1):S43.
We carried out an analysis of the Genetic Analysis Workshop 15 simulated Problem 3 data. We restricted ourselves to the present/absent phenotype. Linkage analysis revealed a very strong signal on chromosome 6. Association analysis revealed additional susceptible loci located on chromosomes 11 and 18. The latter two signals were subsequently verified with linkage analysis – but only after 20 replicates were pooled. Analysis of linkage disequilibrium patterns, in concert with family-based association tests, led us to infer the presence of a second chromosome 6 locus located in the vicinity of single-nucleotide polymorphisms 160–162. These analyses were carried out without knowledge of the model used to generate the simulation.
PMCID: PMC2367550  PMID: 18466542
8.  Linkage and association analyses of principal components in expression data 
BMC Proceedings  2007;1(Suppl 1):S46.
Performing linkage and association analyses on a large set of correlated data presents an interesting set of problems. In the current setting, we have 3554 expression levels from lymphoblastoid cell lines in 194 individuals from 14 three-generation Utah CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees. We formed multivariate expression phenotypes from six sets of genes. These consisted of a set of genes identified by the data providers as showing common linkage to a region of chromosome 14, as well as five other sets suggested by ontological evidence. Using principal-component analyses, we generated seven quantitative phenotypes for expression levels from these six sets of genes. We performed quantitative genome linkage screens on these traits using the expression traits from the third generation of each pedigree. As expected, the strongest linkage signal was achieved when the trait under analysis was the composite of the expressions of genes previously showing linkage to chromosome 14. In particular, this trait produced a LOD score of 5.2 on chromosome 14. The trait also produced LOD scores over 3.5 on chromosomes 1, 7, 9, and 11; this suggests that these genes may be controlled by additional genetic factors on the genome. Subsequent association analyses on the first two generations of these pedigrees identified two polymorphisms on chromosome 11 as significant after correcting for multiple tests. These results suggest that principal-component analyses are useful for the analysis of pleiotropic loci. Furthermore, we have identified two single-nucleotide polymorphisms that may influence the expression of multiple genes linked to chromosome 14.
PMCID: PMC2367470  PMID: 18466545
9.  Gene × gene and gene × environment interactions for complex disorders 
BMC Proceedings  2007;1(Suppl 1):S72.
The restricted partition method (RPM) provides a way to detect qualitative factors (e.g. genotypes, environmental exposures) associated with variation in quantitative or binary phenotypes, even if the contribution is predominantly an interaction displaying little or no signal in univariate analyses. The RPM provides a model (possibly non-linear) of the relationship between the predictor covariates and the phenotype as well as measures of statistical and clinical significance for the model.
Blind to the generating model, we used the RPM to screen a data set consisting 1500 unrelated cases and 2000 unrelated controls from Replicate 1 of the Genetic Analysis Workshop 15 Problem 3 data for genetic and environmental factors contributing to rheumatoid arthritis (RA) risk. Both univariate and pair-wise analyses were performed using sex, smoking, parental DRB1 HLA microsatellite alleles, and 9187 single-nucleotide polymorphisms genotypes from across the genome. With this approach we correctly identified three genetic loci contributing directly to RA risk, and one quantitative trait locus for the endophenotype IgM level. We did not mistakenly identify any factors not in the generating model. All the factors we found were detectable with univariate RPM analyses. We failed to identify two genetic loci modifying the risk of RA. After breaking the blind, we examined the true modeling factors in the first 50 data replicates and found that we would not have identified the additional factors as important even had we combined all the data from the first 50 replicates in a single data set.
PMCID: PMC2367466  PMID: 18466574

Results 1-9 (9)