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Search Results: 1 - 10 of 221301 matches for " Dana C. Crawford "
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VKORC1 Common Variation and Bone Mineral Density in the Third National Health and Nutrition Examination Survey
Dana C. Crawford,Kristin Brown-Gentry,Mark J. Rieder
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015088
Abstract: Osteoporosis, defined by low bone mineral density (BMD), is common among postmenopausal women. The distribution of BMD varies across populations and is shaped by both environmental and genetic factors. Because the candidate gene vitamin K epoxide reductase complex subunit 1 (VKORC1) generates vitamin K quinone, a cofactor for the gamma-carboxylation of bone-related proteins such as osteocalcin, we hypothesized that VKORC1 genetic variants may be associated with BMD and osteoporosis in the general population. To test this hypothesis, we genotyped six VKORC1 SNPs in 7,159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a nationally representative sample linked to health and lifestyle variables including BMD, which was measured using dual energy x-ray absorptiometry (DEXA) on four regions of the proximal femur. In adjusted models stratified by race/ethnicity and sex, SNPs rs9923231 and rs9934438 were associated with increased BMD (p = 0.039 and 0.024, respectively) while rs8050894 was associated with decreased BMD (p = 0.016) among non-Hispanic black males (n = 619). VKORC1 rs2884737 was associated with decreased BMD among Mexican-American males (n = 795; p = 0.004). We then tested for associations between VKORC1 SNPs and osteoporosis, but the results did not mirror the associations observed between VKORC1 and BMD, possibly due to small numbers of cases. This is the first report of VKORC1 common genetic variation associated with BMD, and one of the few reports available that investigate the genetics of BMD and osteoporosis in diverse populations.
Visually integrating and exploring high throughput Phenome-Wide Association Study (PheWAS) results using PheWAS-View
Sarah A Pendergrass, Scott Dudek, Dana C Crawford, Marylyn D Ritchie
BioData Mining , 2012, DOI: 10.1186/1756-0381-5-5
Abstract: We have developed the software PheWAS-View for visually integrating PheWAS results, including information about the SNPs, relevant genes, phenotypes, and the interrelationships between phenotypes, that exist in PheWAS. As a result both the fine grain detail as well as the larger trends that exist within PheWAS results can be elucidated.PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation – and these results can be both explored and presented with PheWAS-View. PheWAS-View is freely available for non-commercial research institutions, for full details see http://ritchielab.psu.edu/ritchielab/software webcite.
Synthesis-View: visualization and interpretation of SNP association results for multi-cohort, multi-phenotype data and meta-analysis
Sarah A Pendergrass, Scott M Dudek, Dana C Crawford, Marylyn D Ritchie
BioData Mining , 2010, DOI: 10.1186/1756-0381-3-10
Abstract: The Synthesis-View software tool was designed to visually synthesize the results of the aforementioned types of studies. Presented herein are multiple examples of the ways Synthesis-View can be used to report results from association studies of DNA variation and phenotypes, including the visual integration of p-values or other metrics of significance, allele frequencies, sample sizes, effect size, and direction of effect.To truly allow a user to visually integrate multiple pieces of information typical of a genetic association study, innovative views are needed to integrate multiple pieces of information. As a result, we have created "Synthesis-View" software for the visualization of genotype-phenotype association data in multiple cohorts. Synthesis-View is freely available for non-commercial research institutions, for full details see https://chgr.mc.vanderbilt.edu/synthesisview webcite.Significant GWAS findings are being further investigated for replication and characterization, both in the populations in which the initial GWAS findings were discovered (such as European-Americans) as well as in new cohorts and populations. To increase power, meta-analysis is often used to combine results from multiple research sites. Multiple independent and correlated phenotypic measurements may be included in these analyses, such as measurements of cardiovascular disease and related biomarkers (lipids, inflammation, etc). Many of these studies characterize less than 100 SNPs. Visualization of these data an integral part of interpreting as well as sharing the complex and multi-layered results of these follow-up studies. The software "Synthesis-View" has been developed to visually synthesize multiple pieces of information of interest from these studies with the flexibility to perform multiple types of data comparisons.Synthesis-View was extended from the previous software "LD-Plus" which also uses a flexible data display format of multiple data "tracks" that can be viewed [1]. Wit
Accuracy of Administratively-Assigned Ancestry for Diverse Populations in an Electronic Medical Record-Linked Biobank
Jacob B. Hall, Logan Dumitrescu, Holli H. Dilks, Dana C. Crawford, William S. Bush
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099161
Abstract: Recently, the development of biobanks linked to electronic medical records has presented new opportunities for genetic and epidemiological research. Studies based on these resources, however, present unique challenges, including the accurate assignment of individual-level population ancestry. In this work we examine the accuracy of administratively-assigned race in diverse populations by comparing assigned races to genetically-defined ancestry estimates. Using 220 ancestry informative markers, we generated principal components for patients in our dataset, which were used to cluster patients into groups based on genetic ancestry. Consistent with other studies, we find a strong overall agreement (Kappa = 0.872) between genetic ancestry and assigned race, with higher rates of agreement for African-descent and European-descent assignments, and reduced agreement for Hispanic, East Asian-descent, and South Asian-descent assignments. These results suggest caution when selecting study samples of non-African and non-European backgrounds when administratively-assigned race from biobanks is used.
Characterization of Genome-Wide Association-Identified Variants for Atrial Fibrillation in African Americans
Jessica T. Delaney, Janina M. Jeff, Nancy J. Brown, Mias Pretorius, Henry E. Okafor, Dawood Darbar, Dan M. Roden, Dana C. Crawford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032338
Abstract: Background Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown. Methodology/Principal Findings We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r2<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13–0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59–7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46–45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls. Conclusions/Significance Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.
Identifying Host Genetic Risk Factors in the Context of Public Health Surveillance for Invasive Pneumococcal Disease
Jairam R. Lingappa, Logan Dumitrescu, Shanta M. Zimmer, Ruth Lynfield, Janet M. McNicholl, Nancy E. Messonnier, Cynthia G. Whitney, Dana C. Crawford
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023413
Abstract: Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p = 0.007) in EA and 5′ flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p = 0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p≤0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases.
Variation in LPA Is Associated with Lp(a) Levels in Three Populations from the Third National Health and Nutrition Examination Survey
Logan Dumitrescu,Kimberly Glenn,Kristin Brown-Gentry,Cynthia Shephard,Michelle Wong,Mark J. Rieder,Joshua D. Smith,Deborah A. Nickerson,Dana C. Crawford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016604
Abstract: The distribution of lipoprotein(a) [Lp(a)] levels can differ dramatically across diverse racial/ethnic populations. The extent to which genetic variation in LPA can explain these differences is not fully understood. To explore this, 19 LPA tagSNPs were genotyped in 7,159 participants from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a diverse population-based survey with DNA samples linked to hundreds of quantitative traits, including serum Lp(a). Tests of association between LPA variants and transformed Lp(a) levels were performed across the three different NHANES subpopulations (non-Hispanic whites, non-Hispanic blacks, and Mexican Americans). At a significance threshold of p<0.0001, 15 of the 19 SNPs tested were strongly associated with Lp(a) levels in at least one subpopulation, six in at least two subpopulations, and none in all three subpopulations. In non-Hispanic whites, three variants were associated with Lp(a) levels, including previously known rs6919246 (p = 1.18×10?30). Additionally, 12 and 6 variants had significant associations in non-Hispanic blacks and Mexican Americans, respectively. The additive effects of these associated alleles explained up to 11% of the variance observed for Lp(a) levels in the different racial/ethnic populations. The findings reported here replicate previous candidate gene and genome-wide association studies for Lp(a) levels in European-descent populations and extend these findings to other populations. While we demonstrate that LPA is an important contributor to Lp(a) levels regardless of race/ethnicity, the lack of generalization of associations across all subpopulations suggests that specific LPA variants may be contributing to the observed Lp(a) between-population variance.
CRP polymorphisms and chronic kidney disease in the third national health and nutrition examination survey
Adriana M Hung, T Alp Ikizler, Marie R Griffin, Kimberly Glenn, Robert A Greevy, Carlos G Grijalva, Edward D Siew, Dana C Crawford
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-65
Abstract: We used data from 5955 participants from Phase 2 of The Third National Health and Nutrition Examination Survey (1991-1994) to study the association between CRP polymorphisms and CKD prevalence in a population-based sample. The primary outcome was CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min or the presence of albuminuria. Secondary outcomes were the presence of albuminuria (any degree) and continuous eGFR. Six single nucleotide polymorphisms (SNPs) from the CRP gene, rs2808630, rs1205, rs3093066, rs1417938, rs3093058, and rs1800947, were evaluated.CRP rs2808630 AG compared to the referent AA genotype was associated with CKD in non-Hispanic blacks (n = 1649, 293 of whom had CKD) with an adjusted odds ratio (OR) of 3.09 (95% CI 1.65-5.8; p = 0.001). For the secondary outcomes, rs2808630 AG compared to the referent AA genotype was associated with albuminuria with an adjusted OR of 3.07 (95% CI 1.59-5.94; p = 0.002), however not with eGFR. There was no association between the SNPs and CKD, albuminuria or eGFR in non-Hispanic whites or Mexicans Americans.In this cross-sectional study, the 3' flanking CRP gene variant rs2808630 was associated with CKD, mainly through its association with albuminuria in the non-Hispanic blacks. Despite not finding an association with eGFR, our results support our previous study demonstrating an association between CRP gene variant rs2808630 and CKD progression in a longitudinal cohort of African American with hypertensive kidney disease.Chronic kidney disease (CKD) represents a major public health problem worldwide. Even in its early stages, CKD is associated with poor outcomes and premature death mainly due to cardiovascular causes [1,2]. Familial aggregation of CKD and end stage renal disease (ESRD) have been reported in populations throughout the world for all types of nephropathy, underscoring the importance of genetic factors [3-7]. There also appears to be genetic predisposition towards faster progression to
Knowledge-Driven Multi-Locus Analysis Reveals Gene-Gene Interactions Influencing HDL Cholesterol Level in Two Independent EMR-Linked Biobanks
Stephen D. Turner,Richard L. Berg,James G. Linneman,Peggy L. Peissig,Dana C. Crawford,Joshua C. Denny,Dan M. Roden,Catherine A. McCarty,Marylyn D. Ritchie,Russell A. Wilke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019586
Abstract: Genome-wide association studies (GWAS) are routinely being used to examine the genetic contribution to complex human traits, such as high-density lipoprotein cholesterol (HDL-C). Although HDL-C levels are highly heritable (h2~0.7), the genetic determinants identified through GWAS contribute to a small fraction of the variance in this trait. Reasons for this discrepancy may include rare variants, structural variants, gene-environment (GxE) interactions, and gene-gene (GxG) interactions. Clinical practice-based biobanks now allow investigators to address these challenges by conducting GWAS in the context of comprehensive electronic medical records (EMRs). Here we apply an EMR-based phenotyping approach, within the context of routine care, to replicate several known associations between HDL-C and previously characterized genetic variants: CETP (rs3764261, p = 1.22e-25), LIPC (rs11855284, p = 3.92e-14), LPL (rs12678919, p = 1.99e-7), and the APOA1/C3/A4/A5 locus (rs964184, p = 1.06e-5), all adjusted for age, gender, body mass index (BMI), and smoking status. By using a novel approach which censors data based on relevant co-morbidities and lipid modifying medications to construct a more rigorous HDL-C phenotype, we identified an association between HDL-C and TRIB1, a gene which previously resisted identification in studies with larger sample sizes. Through the application of additional analytical strategies incorporating biological knowledge, we further identified 11 significant GxG interaction models in our discovery cohort, 8 of which show evidence of replication in a second biobank cohort. The strongest predictive model included a pairwise interaction between LPL (which modulates the incorporation of triglyceride into HDL) and ABCA1 (which modulates the incorporation of free cholesterol into HDL). These results demonstrate that gene-gene interactions modulate complex human traits, including HDL cholesterol.
Admixture Mapping and Subsequent Fine-Mapping Suggests a Biologically Relevant and Novel Association on Chromosome 11 for Type 2 Diabetes in African Americans
Janina M. Jeff, Loren L. Armstrong, Marylyn D. Ritchie, Joshua C. Denny, Abel N. Kho, Melissa A. Basford, Wendy A. Wolf, Jennifer A. Pacheco, Rongling Li, Rex L. Chisholm, Dan M. Roden, M. Geoffrey Hayes, Dana C. Crawford
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086931
Abstract: Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10?8 by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.
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