Integrative analysis of 111 reference human epigenomes

Nature, Journal Year: 2015, Volume and Issue: 518(7539), P. 317 - 330

Published: Feb. 17, 2015

The reference human genome sequence set the stage for studies of genetic variation and its association with disease, but epigenomic lack a similar reference. To address this need, NIH Roadmap Epigenomics Consortium generated largest collection so far epigenomes primary cells tissues. Here we describe integrative analysis 111 as part programme, profiled histone modification patterns, DNA accessibility, methylation RNA expression. We establish global maps regulatory elements, define modules coordinated activity, their likely activators repressors. show that disease- trait-associated variants are enriched in tissue-specific marks, revealing biologically relevant cell types diverse traits, providing resource interpreting molecular basis disease. Our results demonstrate central role information understanding gene regulation, cellular differentiation

Language: Английский

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Genetic effects on gene expression across human tissues

Nature, Journal Year: 2017, Volume and Issue: 550(7675), P. 204 - 213

Published: Oct. 10, 2017

Characterization of the molecular function human genome and its variation across individuals is essential for identifying cellular mechanisms that underlie genetic traits diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize in gene expression levels diverse tissues body, many which are not easily accessible. Here we describe effects on 44 tissues. We find local affects majority genes, further identify inter-chromosomal 93 genes 112 loci. On basis identified effects, patterns tissue specificity, compare distal evaluate functional properties effects. also demonstrate multi-tissue, multi-individual data can be used pathways affected by disease-associated variation, enabling a mechanistic interpretation regulation disease.

Language: Английский

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An atlas of genetic correlations across human diseases and traits

Nature Genetics, Journal Year: 2015, Volume and Issue: 47(11), P. 1236 - 1241

Published: Sept. 28, 2015

Language: Английский

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10 Years of GWAS Discovery: Biology, Function, and Translation

The American Journal of Human Genetics, Journal Year: 2017, Volume and Issue: 101(1), P. 5 - 22

Published: July 1, 2017

Language: Английский

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An Expanded View of Complex Traits: From Polygenic to Omnigenic

Cell, Journal Year: 2017, Volume and Issue: 169(7), P. 1177 - 1186

Published: June 1, 2017

Language: Английский

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Partitioning heritability by functional annotation using genome-wide association summary statistics

Nature Genetics, Journal Year: 2015, Volume and Issue: 47(11), P. 1228 - 1235

Published: Sept. 28, 2015

Language: Английский

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Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Nature Genetics, Journal Year: 2019, Volume and Issue: 51(3), P. 414 - 430

Published: Feb. 28, 2019

Language: Английский

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Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(4), P. 2133 - 2223

Published: Aug. 1, 2018

The 1921 discovery of insulin was a Big Bang from which vast and expanding universe research into action resistance has issued. In the intervening century, some discoveries have matured, coalescing solid fertile ground for clinical application; others remain incompletely investigated scientifically controversial. Here, we attempt to synthesize this work guide further mechanistic investigation inform development novel therapies type 2 diabetes (T2D). rational such necessitates detailed knowledge one key pathophysiological processes involved in T2D: resistance. Understanding resistance, turn, requires normal action. review, both physiology pathophysiology are described, focusing on three target tissues: skeletal muscle, liver, white adipose tissue. We aim develop an integrated physiological perspective, placing intricate signaling effectors that carry out cell-autonomous response context tissue-specific functions generate coordinated organismal response. First, section II, effects direct, tissue reviewed, beginning at receptor working downstream. Section III considers critical underappreciated role crosstalk whole body action, especially essential interaction between lipolysis hepatic gluconeogenesis. is then described IV. Special attention given pathways become resistant setting chronic overnutrition, alternative explanation phenomenon ‟selective resistanceˮ presented. Sections V, VI, VII critically examine evidence against several putative mediators V reviews linking bioactive lipids diacylglycerol, ceramide, acylcarnitine resistance; VI impact nutrient stresses endoplasmic reticulum mitochondria discusses non-cell autonomous factors proposed induce including inflammatory mediators, branched-chain amino acids, adipokines, hepatokines. Finally, VIII, propose model links these final common metabolite-driven gluconeogenesis ectopic lipid accumulation.

Language: Английский

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Immunopathology of multiple sclerosis

Nature reviews. Immunology, Journal Year: 2015, Volume and Issue: 15(9), P. 545 - 558

Published: Aug. 7, 2015

Language: Английский

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Multiple Sclerosis

New England Journal of Medicine, Journal Year: 2018, Volume and Issue: 378(2), P. 169 - 180

Published: Jan. 10, 2018

Multiple sclerosis affects more than 2 million people worldwide and is currently incurable. A number of interventions to modify the course multiple have been developed that offer new insight into disease mechanisms.

Language: Английский

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