ORCID Profile
0000-0002-7892-193X
Current Organisation
University of North Carolina at Chapel Hill
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1161/CIRCGENETICS.116.001572
Abstract: The burden of subclinical atherosclerosis in asymptomatic in iduals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77 P =1×10 − 11 ). Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2020
DOI: 10.1101/2020.02.02.20020065
Abstract: Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 25-11-2027
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Springer Science and Business Media LLC
Date: 29-06-2021
DOI: 10.1186/S13059-021-02398-9
Abstract: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Leveraging DNA methylation and SNP data from more than 40,000 in iduals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
DOI: 10.1038/S41467-018-07340-5
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 in iduals for cIMT, and 48,434 in iduals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2021
Publisher: Elsevier BV
Date: 09-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2021
DOI: 10.1161/CIRCGEN.120.003258
Abstract: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic in iduals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. We performed meta-analyses of genome-wide association studies in up to 2500 T2D in iduals of European ancestry (EA) and 1590 T2D in iduals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 in iduals of EA and 838 in iduals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B ) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1 ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P =2.0×10 -8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations ( P .1×10 -4 ) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in in iduals with T2D.
Location: United States of America
No related grants have been discovered for Laura Raffield.