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"Jackson, Anne"
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Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle
We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height,waist,weight,waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.
Journal Article
Novel Hendra virus variant detected by sentinel surveillance of horses in Australia
We identifi ed and isolated a novel Hendra virus (HeV) variant not detected by routine testing from a horse in Queensland, Australia, that died from acute illness with signs consistent with HeV infection. Using whole-genome sequencing and phylogenetic analysis, we determined the variant had ≈83% nt identity with prototypic HeV. In silico and in vitro comparisons of the receptor-binding protein with prototypic HeV support that the human monoclonal antibody m102.4 used for postexposure prophylaxis and current equine vaccine will be eff ective against this variant. An updated quantitative PCR developed for routine surveillance resulted in subsequent case detection. Genetic sequence consistency with virus detected in grey-headed fl ying foxes suggests the variant circulates at least among this species. Studies are needed to determine infection kinetics, pathogenicity, reservoir-species associations, viral- host coevolution, and spillover dynamics for this virus. Surveillance and biosecurity practices should be updated to acknowledge HeV spillover risk across all regions frequented by fl ying foxes.
Journal Article
Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study
Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005
Journal Article
Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci
Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.
The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms.
Journal Article
The basics of atoms and molecules
This is a detailed introduction to matter, the elements of the periodic table, atoms, electrons, reactions and bonding, and radioactivity. This volume provides young adults with chemistry examples that reflect their real-world. Key terms, easy experiments, and clear illustrations guide students through subatomic explorations. A chapter about Niels Bohr and his model for the atom honors his contribution to the understanding of atomic structure. Tools and techniques, such as a scanning tunneling microscope, Rutherford's gold foil experiment, and a mass spectrometer, help readers to gain a comprehensive understanding of atoms and molecules.
BOOK
Assessing the potential causal effects of 1099 plasma metabolites on 2099 binary disease endpoints
Metabolites are small molecules that are useful for estimating disease risk and elucidating disease biology. Here, we perform two-sample Mendelian randomization to systematically infer the potential causal effects of 1099 plasma metabolites measured in 6136 Finnish men from the METSIM study on risk of 2099 binary disease endpoints measured in 309,154 Finnish individuals from FinnGen. We find evidence for 282 putative causal effects of 70 metabolites on 183 disease endpoints. We also identify 25 metabolites with potential causal effects across multiple disease domains, including ascorbic acid 2-sulfate affecting 26 disease endpoints in 12 disease domains. Our study suggests that N-acetyl-2-aminooctanoate and glycocholenate sulfate affect risk of atrial fibrillation through two distinct metabolic pathways and that N-methylpipecolate may mediate the putative causal effect of N6,N6-dimethyllysine on anxious personality disorder.
Metabolites can be used to estimate disease risk. Here, the authors use Mendelian randomization to infer the potential causal effects of 1099 plasma metabolites on the risk of 2099 binary disease endpoints.
Journal Article