Are there mappable genes for family resemblance for the magnitude of intra-individual variation in systolic blood pressure?

BACKGROUND: The genetic regulation of variation in intra-individual fluctuations in systolic blood pressure over time is poorly understood. Analysis of the magnitude of the average fluctuation of a person's systolic blood pressure around his or her age-adjusted trend line, however, shows moderate, albeit significant, family resemblance in Cohort 1 of the Framingham Heart Study. To determine whether genomic regions affecting this phenotype could be identified, we pursued a "model-free" multipoint quantitative linkage analysis. RESULTS: Two different linkage methods revealed multiple nominally significant signals, two to four of which are "replicated" in Cohort 2. When both cohorts are assembled into extended pedigrees, three linkage signals remain nominally significant by one or both methods. CONCLUSION: Any or all of the genomic regions in the vicinity of D5S1456, D11S2359, and D20S470 may contain elements that regulate systolic blood pressure homeostasis

Identifying cryptic population structure in multigenerational pedigrees in a Mexican American sample

Cryptic population structure can increase both type I and type II errors. This is particularly problematic in case-control association studies of unrelated individuals. Some researchers believe that these problems are obviated in families. We argue here that this may not be the case, especially if families are drawn from a known admixed population such as Mexican Americans. We use a principal component approach to evaluate and visualize the results of three different approaches to searching for cryptic structure in the 20 multigenerational families of the Genetic Analysis Workshop 18 (GAW18). Approach 1 uses all family members in the sample to identify what might be considered "outlier" kindreds. Because families are likely to differ in size (in the GAW18 families, there is about a 4-fold difference in the number of typed individuals), approach 2 uses a weighting system that equalizes pedigree size. Approach 3 concentrates on the founders and the "marry-ins" because, in principle, the entire pedigree can be reconstructed with knowledge of the sequence of these unrelated individuals and genome-wide association study (GWAS) data on everyone else (to identify the position of recombinations). We demonstrate that these three approaches can yield very different insights about cryptic structure in a sample of families

Interplay between attenuation- and virulence-factors of Babesia Bovis and their contribution to the establishment of persistent infections in cattle

Bovine babesiosis is an acute and persistent tick-borne global disease caused mainly by the intraerythrocytic apicomplexan parasites Babesia bovis and B. bigemina. B. bovis infected erythrocytes sequester in blood capillaries of the host (cytoadhesion), causing malaria-like neurological signs. Cytoadhesion and antigenic variation in B. bovis are linked to the expression of members of the Variant Erythrocyte Surface Antigen (VESA) gene family. Animals that survive acute B. bovis infection and those vaccinated with attenuated strains remain persistently infected, suggesting that B. bovis parasites use immune escape mechanisms. However, attenuated B. bovis parasites do not cause neurological signs in vaccinated animals, indicating that virulence or attenuation factors play roles in modulating parasite virulence phenotypes. Artificial overexpression of the SBP2t11 protein, a defined attenuation factor, was associated with reduced cytoadhesion, suggesting a role for this protein as a key modulator of virulence in the parasite. Hereby, we propose a model that might be functional in the modulation of B. bovis virulence and persistence that relies on the interplay among SBP2t, VESA proteins, cytoadhesion, and the immune responses of the host. Elucidation of mechanisms used by the parasite to establish persistent infection will likely contribute to the design of new methods for the control of bovine babesiosis

Linkage and association analyses of principal components in expression data

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

Development of a 5-Component Balance for Water Tunnel Applications

The principal objective of this research/development effort was to develop a multi-component strain gage balance to measure both static and dynamic forces and moments on models tested in flow visualization water tunnels. A balance was designed that allows measuring normal and side forces, and pitching, yawing and rolling moments (no axial force). The balance mounts internally in the model and is used in a manner typical of wind tunnel balances. The key differences between a water tunnel balance and a wind tunnel balance are the requirement for very high sensitivity since the loads are very low (typical normal force is 90 grams or 0.2 lbs), the need for water proofing the gage elements, and the small size required to fit into typical water tunnel models. The five-component balance was calibrated and demonstrated linearity in the responses of the primary components to applied loads, very low interactions between the sections and no hysteresis. Static experiments were conducted in the Eidetics water tunnel with delta wings and F/A-18 models. The data were compared to forces and moments from wind tunnel tests of the same or similar configurations. The comparison showed very good agreement, providing confidence that loads can be measured accurately in the water tunnel with a relatively simple multi-component internal balance. The success of the static experiments encouraged the use of the balance for dynamic experiments. Among the advantages of conducting dynamic tests in a water tunnel are less demanding motion and data acquisition rates than in a wind tunnel test (because of the low-speed flow) and the capability of performing flow visualization and force/moment (F/M) measurements simultaneously with relative simplicity. This capability of simultaneous flow visualization and for F/M measurements proved extremely useful to explain the results obtained during these dynamic tests. In general, the development of this balance should encourage the use of water tunnels for a wider range of quantitative and qualitative experiments, especially during the preliminary phase of aircraft design

Detecting population stratification using related individuals

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

Power and false-positive rates for the restricted partition method (RPM) in a large candidate gene data set

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