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Search Results: 1 - 10 of 463424 matches for " Rasika A. Mathias? "
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Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis
Mary J. Emond?,Tin Louie?,Julia Emerson?,Jessica X. Chong?,Rasika A. Mathias,Michael R. Knowles?,Mark J. Rieder?,Holly K. Tabor?,Debbie A. Nickerson?,Kathleen C. Barnes
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005273
Abstract: Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.
Adaptive Evolution of the FADS Gene Cluster within Africa
Rasika A. Mathias, Wenqing Fu, Joshua M. Akey, Hannah C. Ainsworth, Dara G. Torgerson, Ingo Ruczinski, Susan Sergeant, Kathleen C. Barnes, Floyd H. Chilton
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044926
Abstract: Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ~85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60–80 kya.
On the Analysis of Genome-Wide Association Studies in Family-Based Designs: A Universal, Robust Analysis Approach and an Application to Four Genome-Wide Association Studies
Sungho Won,Jemma B. Wilk,Rasika A. Mathias,Christopher J. O'Donnell,Edwin K. Silverman,Kathleen Barnes,George T. O'Connor,Scott T. Weiss,Christoph Lange
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000741
Abstract: For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1) in 4 genome-wide association studies.
Targeted Deep Resequencing Identifies Coding Variants in the PEAR1 Gene That Play a Role in Platelet Aggregation
Yoonhee Kim, Bhoom Suktitipat, Lisa R. Yanek, Nauder Faraday, Alexander F. Wilson, Diane M. Becker, Lewis C. Becker, Rasika A. Mathias
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064179
Abstract: Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020×10?4); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56×10?4, 2.27×10?7, 5.20×10?5 for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans.
Aquaporin 5 Polymorphisms and Rate of Lung Function Decline in Chronic Obstructive Pulmonary Disease
Nadia N. Hansel,Venkataramana Sidhaye,Nicholas M. Rafaels,Li Gao,Peisong Gao,Renaldo Williams,John E. Connett,Terri H. Beaty,Rasika A. Mathias,Robert A. Wise,Landon S. King,Kathleen C. Barnes
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014226
Abstract: Aquaporin-5 (AQP5) can cause mucus overproduction and lower lung function. Genetic variants in the AQP5 gene might be associated with rate of lung function decline in chronic obstructive pulmonary disease (COPD).
DNA Methylation in an Enhancer Region of the FADS Cluster Is Associated with FADS Activity in Human Liver
Timothy D. Howard, Rasika A. Mathias, Michael C. Seeds, David M. Herrington, James E. Hixson, Lawrence C. Shimmin, Greg A. Hawkins, Matthew Sellers, Hannah C. Ainsworth, Susan Sergeant, Leslie R. Miller, Floyd H. Chilton
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097510
Abstract: Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20:4, n-6), eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18:2, n-6) to AA and α-linolenic acid (ALA, 18:3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5′ to 5′) in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ~15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95×10?46) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities.
A graphical assessment of p-values from sliding window haplotype tests of association to identify asthma susceptibility loci on chromosome 11q
Rasika A Mathias, Peisong Gao, Janet L Goldstein, Alexander F Wilson, Elizabeth W Pugh, Paulette Furbert-Harris, Georgia M Dunston, Floyd J Malveaux, Alkis Togias, Kathleen C Barnes, Terri H Beaty, Shau-Ku Huang
BMC Genetics , 2006, DOI: 10.1186/1471-2156-7-38
Abstract: We present a newly developed tool, Graphical Assessment of Sliding P-values or GrASP, which uses color display to indicate the width of the sliding windows, significance of individual tests, density of SNP coverage and location of known genes that simplifies some of these issues, and use it to identify regions of interest in these data.We demonstrate that GrASP makes it easier to visualize, summarize and prioritize regions of interest from sliding window haplotype analysis, based jointly on the p-value from all the tests from these windows and the building of haplotypes of significance in the region. Using this approach, five regions yielded strong evidence for linkage and association with asthma, including the prior peak linkage region.To search for causal genes for asthma on chromosome 11q, a region previously highlighted in linkage and association studies on African American families by our group, a dense panel of SNPs was genotyped using an Illumina? fine mapping panel in these African American subjects. The sliding window approach that has gained much favor in recent years [1-6] to test for association between SNPs and haplotypes in this region was adapted to analyze case-parent trios and case-control data because it is a simple and efficient way to screen a region of dense genotyping. Given an ordered set of markers (1, 2, 3,....n), sliding windows of overlapping haplotypes are tested in sequence, i.e. markers 1-2-3 are treated as a single haplotype, then markers 2-3-4 are treated as a single haplotype, then markers 3-4-5, etc. Haplotypes of varying sizes (i.e. 2-, 3-, 4-SNP haplotypes, etc.) can be assessed. When large numbers of SNPs are used, this approach generates large numbers of non-independent statistical tests, and visualizing and interpreting these multiple tests can become daunting. Currently, it is common practice to use some form of summary measure (such as the minimum p-value of all sliding windows or windows of a particular size that include any
A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
Rasika A Mathias, Yoonhee Kim, Heejong Sung, Lisa R Yanek, VJ Mantese, J Enrique Hererra-Galeano, Ingo Ruczinski, Alexander F Wilson, Nauder Faraday, Lewis C Becker, Diane M Becker
BMC Medical Genomics , 2010, DOI: 10.1186/1755-8794-3-22
Abstract: Clinical data on 37 agonist-induced platelet function phenotypes were evaluated before and after a 2-week trial of ASA (81 mg/day) in 1231 European American and 846 African American healthy subjects with a family history of premature CAD. Principal component analysis was performed to minimize the number of independent factors underlying the covariance of these various phenotypes. Multi-point sib-pair based linkage analysis was performed using a microsatellite marker set, and single-SNP association tests were performed using markers from the Illumina 1 M genotyping chip from deCODE Genetics, Inc. All analyses were performed separately within each ethnic group.Several genomic regions appear to be linked to ASA response factors: a 10 cM region in African Americans on chromosome 5q11.2 had several STRs with suggestive (p-value < 7 × 10-4) and significant (p-value < 2 × 10-5) linkage to post aspirin platelet response to ADP, and ten additional factors had suggestive evidence for linkage (p-value < 7 × 10-4) to thirteen genomic regions. All but one of these factors were aspirin response variables. While the strength of genome-wide SNP association signals for factors showing evidence for linkage is limited, especially at the strict thresholds of genome-wide criteria (N = 9 SNPs for 11 factors), more signals were considered significant when the association signal was weighted by evidence for linkage (N = 30 SNPs).Our study supports the hypothesis that platelet phenotypes in response to ASA likely have genetic control and the combined approach of linkage and association offers an alternative approach to prioritizing regions of interest for subsequent follow-up.Platelet activation plays a critical role in atherothrombotic diseases such as acute myocardial infarction (MI) and stroke. Aspirin (acetylsalicylic acid [ASA]) is a mainstay of both primary and secondary prevention of MI and stroke [1]. ASA inhibits cyclooxygenase-1 (COX-1) and thromboxane-dependent platelet activatio
Calibrating Remotely Sensed Ocean Chlorophyll Data: An Application of the Blending Technique in Three Dimensions (3D)  [PDF]
Mathias A. Onabid
Open Journal of Marine Science (OJMS) , 2017, DOI: 10.4236/ojms.2017.71014
Abstract: In this article, the extension to three dimensions (3D) of the blending technique that has been widely used in two dimensions (2D) to calibrate ocean chlorophyll is presented. The results thus obtained revealed a very high degree of efficiency when predicting observed values of ocean chlorophyll. The mean squared difference between the predicted and observed values of ocean chlorophyll when 3D technique was used fell far below the tolerance level which was set to the difference between satellite and observed in-situ values. The resulting blended field did not only provide better predictions of the in situ observations in areas where bottle samples cannot be obtained but also provided a smooth variation of the distribution of ocean chlorophyll throughout the year. An added advantage is its computational efficiency since data that would have been treated at least four times would be treated only once. With the advent of these results, it is believed that the modelling of the ocean life cycle will become more realistic.
The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans
Rasika A Mathias, Susan Sergeant, Ingo Ruczinski, Dara G Torgerson, Christina E Hugenschmidt, Meghan Kubala, Dhananjay Vaidya, Bhoom Suktitipat, Julie T Ziegler, Priscilla Ivester, Douglas Case, Lisa R Yanek, Barry I Freedman, Megan E Rudock, Kathleen C Barnes, Carl D Langefeld, Lewis C Becker, Donald W Bowden, Diane M Becker, Floyd H Chilton
BMC Genetics , 2011, DOI: 10.1186/1471-2156-12-50
Abstract: In this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 × 10-48) and lower DGLA levels (p = 9.80 × 10-11) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (FADS) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 × 10-16 in African Americans, 2.68 × 10-23 in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with enhanced conversion of DGLA to AA, on enzymatic efficiency was similar in both groups.We conclude that the impact of FADS genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA.Levels of unsaturated fatty acids influence key cellular functions necessary for life including the fluidity of membranes, the function of membrane-associated proteins, signal transduction events, the transcription of proteins and the synthesis of lipid-derived bioactive molecules. Seminal studies published in the 1930's by Burr, Burr and Miller [1] demonstrated that the medium chain unsaturated fatty acid (MC-PUFA), linoleic acid (C18:2,ω6; LA), is essential for the survival and health of rats. Later studies demonstrated that LA is 'essential' because it cannot be synthesized de novo in higher animals [2,3], and it is therefore indispensible in the synthesis of the long chain polyunsaturated fatty acids (LC-PUFA), such as arachidonic acid (AA) [4].The conversion of LA to AA occurs thr
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