QTLRel: an R Package for Genome-wide Association Studies in which Relatedness is a Concern

BACKGROUND Existing software for quantitative trait mapping is either not able to model polygenic variation or does not allow incorporation of more than one genetic variance component. Improperly modeling the genetic relatedness among subjects can result in excessive false positives. We have developed an R package, QTLRel, to enable more flexible modeling of genetic relatedness as well as covariates and non-genetic variance components. RESULTS We have successfully used the package to analyze many datasets, including F₃₄ body weight data that contains 688 individuals genotyped at 3105 SNP markers and identified 11 QTL. It took 295 seconds to estimate variance components and 70 seconds to perform the genome scan on an Linux machine equipped with a 2.40GHz Intel(R) Core(TM)2 Quad CPU. CONCLUSIONS QTLRel provides a toolkit for genome-wide association studies that is capable of calculating genetic incidence matrices from pedigrees, estimating variance components, performing genome scans, incorporating interactive covariates and genetic and non-genetic variance components, as well as other functionalities such as multiple-QTL mapping and genome-wide epistasis.This project was supported by NIH grants R01DA021336, R01MH079103 and R21DA024845

QTLRel: An R package for genome-wide association studies in which relatedness is a concern

Abstract Background: Existing software for quantitative trait mapping is either not able to model polygenic variation or does not allow incorporation of more than one genetic variance component. Improperly modeling the genetic relatedness among subjects can result in excessive false positives. We have developed an R package, QTLRel, to enable more flexible modeling of genetic relatedness as well as covariates and non-genetic variance components. Results: We have successfully used the package to analyze many datasets, including F 34 body weight data that contains 688 individuals genotyped at 3105 SNP markers and identified 11 QTL. It took 295 seconds to estimate variance components and 70 seconds to perform the genome scan on an Linux machine equipped with a 2.40GHz Intel(R) Core(TM)2 Quad CPU. Conclusions: QTLRel provides a toolkit for genome-wide association studies that is capable of calculating genetic incidence matrices from pedigrees, estimating variance components, performing genome scans, incorporating interactive covariates and genetic and non-genetic variance components, as well as other functionalities such as multiple-QTL mapping and genome-wide epistasis

Genetic regulatory effects in response to a high-cholesterol, high-fat diet in baboons

Steady-state expression quantitative trait loci (eQTLs) explain only a fraction of disease-associated loci identified through genome-wide association studies (GWASs), while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Using a baboon model, we found hundreds of eQTLs that emerge in adipose, liver, and muscle after prolonged exposure to high dietary fat and cholesterol. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using non-human primate models

Hydrodynamic Detonation Instability in Electroweak and QCD Phase Transitions

The hydrodynamic stability of deflagration and detonation bubbles for a first order electroweak and QCD phase transition has been discussed recently with the suggestion that detonations are stable. We examine here the case of a detonation more carefully. We find that in front of the bubble wall perturbations do not grow with time, but behind the wall modes exist which grow exponentially. We briefly discuss the possible meaning of this instability.Comment: 12 pages, 3 figures available on request, Latex, FERMILAB--PUB--93/098--

Homozygosity by descent mapping of blood pressure in the Old Order Amish: evidence for sex specific genetic architecture

<p>Abstract</p> <p>Background</p> <p>High blood pressure is a well established risk factor for morbidity and mortality acting through heart disease, stroke and cardiovascular disease. Genome wide scans have linked regions of nearly every human chromosome to blood pressure related traits. We have capitalized on beneficial qualities of the Old Order Amish of Lancaster, PA, a closed founder population with a relatively small number of founders, to perform a genome wide homozygosity by descent mapping scan. Each individual in the study has a non zero probability of consanguinity. Systolic and diastolic blood pressures are shown to have appreciable dominance variance components.</p> <p>Results</p> <p>Areas of two chromosomes were identified as suggestive of linkage to SBP and 5 areas to DBP in either the overall or sex specific analyses. The strongest evidence for linkage in the overall sample was to Chromosome 18q12 (LOD = 2.6 DBP). Sex specific analyses identified a linkage on Chromosome 4p12-14 (LOD in men only = 3.4 SBP). At Chromosome 2q32-33, an area where we previously reported significant evidence for linkage to DBP using a conventional identity by descent approach, the LOD was 1.4; however an appreciable sex effect was observed with men accounting for most of the linkage (LOD in men only = 2.6).</p> <p>Conclusion</p> <p>These results add evidence to a sex specific genetic architecture to blood pressure related traits, particularly in regions of linkage on chromosome 2, 4 and 18.</p

Fluctuations and Bubble Dynamics in First-Order Phase Transitions

We numerically examine the effect of thermal fluctuations on a first-order phase transition in 2+1 dimensions. By focusing on the expansion of a single bubble we are able to calculate changes in the bubble wall's velocity as well as changes in its structure relative to the standard case where the bubble expands into a homogeneous background. Not only does the wall move faster, but the transition from the symmetric to the asymmetric phase is no longer smooth, even for a fairly strong transition. We discuss how these results affect the standard picture of electroweak baryogenesis.Comment: Latex, 30 pages, 11 ps figures, short discussion added in conclusions and minor clarifications, accepted to Phys Rev

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Acknowledgements The authors would like to acknowledge Dr David A. Blizard for his role in the development of the ideas that led to this study and feedback on the manuscript, Professor Helen Macdonald for valuable advice on study design, Dr Leslie R. Noble for help with the UK Biobank data, and Dr Joseph P. Gyekis for help genotyping cohort 2 mice. The authors would like to acknowledge funding from the University of Aberdeen for the Maxwell computer cluster, the Elphinstone and IMS studentship for AIHC; a Schweppe Foundation Career Development Award (AAP), and the NIH (NIAMS (AL: R01AR056280) and NIDA (AAP:R01DA021336, AAP:R21DA024845, AAP:T32MH020065, NMG:F31DA03635803), NIGMS (NMG:T32GM007197), NHGRI (MA:R01HG002899))Peer reviewedPostprin

Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS

Insights on uranium uptake mechanisms by ion exchange resins with chelating functionalities: Chelation vs. anion exchange

X-ray absorption fine structure analysis has been successfully used to determine the coordination environment and therefore uptake mechanism towards the uranyl cation for a selection of commercially available ion exchange resins in non-saline and saline conditions ([Cl−] = 22.7 g L−1, 0.64 M) similar to those found in sea water. The resins tested were Purolite S985, S910 and S957, Dowex M4195, Ps-EDA, Ps-DETA and Ps-PEHA, which contain polyamine, amidoxime, mixed sulfonic/phosphonic acid, bispicolylamine, ethylenediamine, diethylenetriamine and pentaethylenehexamine functional groups, respectively. Purolite S910 and S957 were both found to extract the uranyl cation through a chelation mechanism. The uranium coordination environment on uranyl loaded Purolite S910 was found to be either tetra- or hexa-coordinate in the equatorial plane, with a 2:1 ratio of amidoxime:uranium in the fit suggesting either monodentate or η2 coordination by two amidoxime groups. The uranium environment for uranyl loaded Purolite S957 was found to be tetra-coordinate in the equatorial plane, with both sulfonic and phosphonic acid groups being involved in sorption. The presence of chloride in the loading solution had no effect on the uranyl coordination environment observed on any of the resins. In contrast, Dowex M4195, Purolite S985, Ps-EDA, Ps-DETA and Ps-PEHA exhibited an anion exchange mechanism for uranyl uptake as the corresponding extended X-ray absorption fine structure (EXAFS) data best fit a [UO2(SO4)3]4− structure

The effect of contaminants on the application of polyamine functionalised ion exchange resins for uranium extraction from sulfate based mining process waters

Three in-house produced polyamine functionalised ion exchange resins and Purolite S985 (a commercial ion exchange resin) have been assessed for their ability to extract UO22+ from a variety of aqueous matrices applicable to current and potential future uranium mining processes. The uptake of common contaminant species in uranium processing liquors at variable acid concentrations has been assessed, with Al3+ and MoO42− showing the most extraction, with AsO43−, Eu3+ and Fe3+ showing extractions >10% at low [H+]. Extraction of MoO42−, AsO43−, Eu3+ and Fe3+ was seen to decrease with increasing [H+]. The impact of increasing [Cl−] on UO22+ and Fe3+ extraction has been determined. Fe3+ showed low extractions by all resins, with no dependence on [Cl−]. In contrast, increasing suppression of UO22+ uptake was seen with increasing [Cl−] up to 80 g L−1, with extraction remaining constant beyond this [Cl−]. At high [Cl−] (>50 g L−1) Purolite S985 was seen to remove UO22+ from solution more effectively than all synthesised polyamine resins. The presence of Fe3+ in solution was seen to suppress UO22+ uptake by around 10% when [Fe3+]/[UO22+] increased from 0 to 2. Fe3+ extraction by all studied resins was promoted by the presence of UO22+ in solution. This was most prevalent with Purolite S985, with an extraction of 30% for [Fe3+]/[UO22+] = 2 by Purolite S985. All resins were tested using a process water from a uranium mine and have shown an ability to selectively extract UO22+ from such solutions, with the best synthetic resin recovering 15.7% more uranium than Purolite S985