Epistatic Module Detection for Case-Control Studies: A Bayesian Model with a Gibbs Sampling Strategy

The detection of epistatic interactive effects of multiple genetic variants on the susceptibility of human complex diseases is a great challenge in genome-wide association studies (GWAS). Although methods have been proposed to identify such interactions, the lack of an explicit definition of epistatic effects, together with computational difficulties, makes the development of new methods indispensable. In this paper, we introduce epistatic modules to describe epistatic interactive effects of multiple loci on diseases. On the basis of this notion, we put forward a Bayesian marker partition model to explain observed case-control data, and we develop a Gibbs sampling strategy to facilitate the detection of epistatic modules. Comparisons of the proposed approach with three existing methods on seven simulated disease models demonstrate the superior performance of our approach. When applied to a genome-wide case-control data set for Age-related Macular Degeneration (AMD), the proposed approach successfully identifies two known susceptible loci and suggests that a combination of two other loci—one in the gene SGCD and the other in SCAPER—is associated with the disease. Further functional analysis supports the speculation that the interaction of these two genetic variants may be responsible for the susceptibility of AMD. When applied to a genome-wide case-control data set for Parkinson's disease, the proposed method identifies seven suspicious loci that may contribute independently to the disease

Fire Ant Decapitating Fly Cooperative Release Programs (1994–2008): Two Pseudacteon Species, P. tricuspis and P. curvatus, Rapidly Expand Across Imported Fire Ant Populations in the Southeastern United States

Natural enemies of the imported fire ants, Solenopsis invicta Buren S. richteri Forel (Hymenoptera: Formicidae), and their hybrid, include a suite of more than 20 fire ant decapitating phorid flies from South America in the genus Pseudacteon. Over the past 12 years, many researchers and associates have cooperated in introducing several species as classical or self-sustaining biological control agents in the United States. As a result, two species of flies, Pseudacteon tricuspis Borgmeier and P. curvatus Borgmeier (Diptera: Phoridae), are well established across large areas of the southeastern United States. Whereas many researchers have published local and state information about the establishment and spread of these flies, here distribution data from both published and unpublished sources has been compiled for the entire United States with the goal of presenting confirmed and probable distributions as of the fall of 2008. Documented rates of expansion were also used to predict the distribution of these flies three years later in the fall of 2011. In the fall of 2008, eleven years after the first successful release, we estimate that P. tricuspis covered about 50% of the fire ant quarantined area and that it will occur in almost 65% of the quarantine area by 2011. Complete coverage of the fire ant quarantined area will be delayed or limited by this species' slow rate of spread and frequent failure to establish in more northerly portions of the fire ant range and also, perhaps, by its preference for red imported fire ants (S. invicta). Eight years after the first successful release of P. curvatus, two biotypes of this species (one biotype occurring predominantly in the black and hybrid imported fire ants and the other occurring in red imported fire ants) covered almost 60% of the fire ant quarantined area. We estimate these two biotypes will cover almost 90% of the quarantine area by 2011 and 100% by 2012 or 2013. Strategic selection of several distributional gaps for future releases will accelerate complete coverage of quarantine areas. However, some gaps may be best used for the release of additional species of decapitating flies because establishment rates may be higher in areas without competing species

Matrix Metalloproteinases in Cytotoxic Lymphocytes Impact on Tumour Infiltration and Immunomodulation

To efficiently combat solid tumours, endogenously or adoptively transferred cytotoxic T cells and natural killer (NK) cells, need to leave the vasculature, traverse the interstitium and ultimately infiltrate the tumour mass. During this locomotion and migration in the three dimensional environment many obstacles need to be overcome, one of which is the possible impediment of the extracellular matrix. The first and obvious one is the sub-endothelial basement membrane but the infiltrating cells will also meet other, both loose and tight, matrix structures that need to be overridden. Matrix metalloproteinases (MMPs) are believed to be one of the most important endoprotease families, with more than 25 members, which together have function on all known matrix components. This review summarizes what is known on synthesis, expression patterns and regulation of MMPs in cytotoxic lymphocytes and their possible role in the process of tumour infiltration. We also discuss different functions of MMPs as well as the possible use of other lymphocyte proteases for matrix degradation

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Efficacy of the InvictDetectTM Immunostrip® to Taxonomically Identify the Red Imported Fire Ant, Solenopsis invicta, Using A Single Worker Ant

The early detection and identification of the red imported fire ant Solenopsis invicta are crucial to intercepting and preventing it from becoming established in new areas. Unfortunately, the visual identification of fire ants to species is difficult and ant samples must often be couriered to an expert for positive identification, which can delay control interventions. A lateral flow immunoassay that provides a rapid and portable method for the identification of S. invicta ants was developed and commercialized, and it is available from Agdia, Inc. under the trade name InvictDetectTM. While the test was 100% accurate when using the recommended minimum sample of three ant workers, InvictDetectTM was field tested for the first time while using homogenates prepared from single S. invicta workers to determine the effectiveness of the method under these non-recommended conditions. Disregarding social form, the false negative rate was 25.5% for an initial single worker ant test and 10% after a repeat test was performed. The InvictDetectTM false negative response was independent of worker weight. Though InvictDetectTM requires a minimum of three worker ants, the test improves upon current identification methods because it can be conducted in the field, be completed in 10&ndash;30 min, and requires no special training or expertise

Floods and cold front passages: Impacts on coastal marshes in a river diversion setting (Wax Lake Delta Area, Louisiana)

Diversion of the Mississippi River is considered the most effective way of offsetting Louisiana\u27s coastal plain land loss. The Wax Lake delta, a man-made diversion that represents mostly sand-rich distributary mouth bar deposits, is cited as a model for land building from a large river diversion. The fine-grained suspended load is mostly deposited outside of the delta. Numerical simulations of diversion delta building focus primarily on sand deposition. The fine-grained suspended load is only secondarily considered. Research results reported here suggest that natural processes associated with the synergistic relationship between floods and cold front passages can effectively distribute suspended sediments to maintain and rebuild wetlands outside the sand-rich delta. Measurements (fixed acoustic Doppler current profilers) of current speed, current direction, and water level in a mainland marsh channel, north of Atchafalaya Bay, indicate that as cold fronts approach, local water levels can be elevated by as much as 1 m, and normal discharge into the bay is reversed so that flow is into the coastal plain marshes. LIDAR bank elevations indicate that overbank flow is initiated by these events. Streamside sediment accretion (2-y monitoring period) using feldspar plots indicates up to 6.8 cm. Longer term Cs-137 data reveal an average sediment accretion rate of \u3e1 cm y over 50+ years. Marsh flooding results in denitrification of nitrate in river water plus nutrient uptake resulting in increased plant productivity, considerably greater than for similar coastal plain marshes free of riverine sediment input. Fine-grained suspended sediments are important for rebuilding Louisiana\u27s coastal plain, which is naturally constructed mostly of riverine silt and clay plus organic matter. -

Floods and Cold Front Passages: Impacts on Coastal Marshes in a River Diversion Setting (Wax Lake Delta Area, Louisiana)

Diversion of the Mississippi River is considered the most effective way of offsetting Louisiana\u27s coastal plain land loss. The Wax Lake delta, a man-made diversion that represents mostly sand-rich distributary mouth bar deposits, is cited as a model for land building from a large river diversion. The fine-grained suspended load is mostly deposited outside of the delta. Numerical simulations of diversion delta building focus primarily on sand deposition. The fine-grained suspended load is only secondarily considered. Research results reported here suggest that natural processes associated with the synergistic relationship between floods and cold front passages can effectively distribute suspended sediments to maintain and rebuild wetlands outside the sand-rich delta. Measurements (fixed acoustic Doppler current profilers) of current speed, current direction, and water level in a mainland marsh channel, north of Atchafalaya Bay, indicate that as cold fronts approach, local water levels can be elevated by as much as 1 m, and normal discharge into the bay is reversed so that flow is into the coastal plain marshes. LIDAR bank elevations indicate that overbank flow is initiated by these events. Streamside sediment accretion (2-y monitoring period) using feldspar plots indicates up to 6.8 cm. Longer term Cs-137 data reveal an average sediment accretion rate of \u3e1 cm y over 50+ years. Marsh flooding results in denitrification of nitrate in river water plus nutrient uptake resulting in increased plant productivity, considerably greater than for similar coastal plain marshes free of riverine sediment input. Fine-grained suspended sediments are important for rebuilding Louisiana\u27s coastal plain, which is naturally constructed mostly of riverine silt and clay plus organic matter. -