ORCID Profile
0000-0002-3049-7332
Current Organisations
National Institutes of Health
,
Estonian University of Life Sciences
,
University of Lincoln
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Publisher: Public Library of Science (PLoS)
Date: 12-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
DOI: 10.1161/CIRCGENETICS.116.001482
Abstract: One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=−0.88 P =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47 P =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change 95% confidence interval, 0.83–0.95 P =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=−0.03 [0.16]). The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
Publisher: Public Library of Science (PLoS)
Date: 12-12-2013
Publisher: Public Library of Science (PLoS)
Date: 11-05-2011
Publisher: Springer Science and Business Media LLC
Date: 19-01-2011
Publisher: Springer Science and Business Media LLC
Date: 28-10-2014
DOI: 10.1038/NCOMMS6068
Abstract: Statins effectively lower LDL cholesterol levels in large studies and the observed interin idual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1 , not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2016
DOI: 10.1038/NATURE18608
Abstract: Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5-2.9 days earlier on average), with substantial taxonomic variation (1.1-14.8 days earlier on average).
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 12-09-2013
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Public Library of Science (PLoS)
Date: 16-02-2017
Publisher: Springer Science and Business Media LLC
Date: 22-06-2014
DOI: 10.1038/NG.3014
Publisher: Public Library of Science (PLoS)
Date: 10-06-2013
Publisher: Oxford University Press (OUP)
Date: 03-2012
Publisher: Public Library of Science (PLoS)
Date: 13-09-2016
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1038/GIM.2013.72
Publisher: Elsevier BV
Date: 07-2011
Publisher: Wiley
Date: 06-2016
DOI: 10.1002/CPT.350
Publisher: Springer Science and Business Media LLC
Date: 12-2013
DOI: 10.1038/NBT.2749
Publisher: Oxford University Press (OUP)
Date: 18-08-2015
DOI: 10.1093/IJE/DYV136
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1038/GIM.2012.15
Publisher: Frontiers Media SA
Date: 05-08-2014
Publisher: Springer Science and Business Media LLC
Date: 25-12-2013
DOI: 10.1038/NATURE12873
Publisher: American Association for Cancer Research (AACR)
Date: 04-2020
DOI: 10.1158/1055-9965.EPI-19-0891
Abstract: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96 95% confidence interval (CI) = 0.93–0.98 P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95 95% CI = 0.92–0.97 P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06 95% CI = 1.03–1.08 P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04 95% CI = 1.01–1.07 P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03 95% CI = 1.01–1.06 P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
Publisher: JMIR Publications Inc.
Date: 13-09-2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 10-05-2017
DOI: 10.1126/SCITRANSLMED.AAI8708
Abstract: Numerous associations were discovered between human leukocyte antigen (HLA) variation and a comprehensive set of phenotypes derived from electronic health records.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2014
Publisher: Springer Science and Business Media LLC
Date: 23-07-2019
DOI: 10.1038/S41467-019-10924-4
Abstract: Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species.
Publisher: Public Library of Science (PLoS)
Date: 17-06-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1161/CIRCGENETICS.116.001530
Abstract: Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single-nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [ r ]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=−0.44, P =0.005), high-density lipoprotein (rG=−0.48, P =0.005), systolic blood pressure (rG=0.44, P =0.02), and triglycerides (rG=0.38, P =0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors. The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-04-2013
DOI: 10.1161/CIRCULATIONAHA.112.000604
Abstract: ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in in iduals without cardiac disease. Slow conduction may promote re-entrant arrhythmias. We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 in iduals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE s les 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P =1.2×10 −8 (eMERGE) and P =2.5×10 −20 (CHARGE) and rs6795970 in SCN10A with P =6×10 −6 (eMERGE) and P =5×10 −27 (CHARGE). The other loci were in NFIA , near CDKN1A , and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 “heart-healthy” study population. We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
Location: United States of America
No related grants have been discovered for Josh Denny.