Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease

Science, Journal Year: 2022, Volume and Issue: 376(6589)

Published: April 7, 2022

The human immune system displays substantial variation between individuals, leading to differences in susceptibility autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells 982 healthy subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing type-specific effects on gene expression. subsequently show how eQTLs have dynamic allelic B that are transitioning naïve memory states demonstrate commonly segregating alleles lead interindividual function. Finally, using a Mendelian randomization approach, identify the causal route by which 305 risk contribute disease at cellular level. This work brings together genetic epidemiology scRNA-seq uncover drivers of system.

Language: Английский

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A compendium of uniformly processed human gene expression and splicing quantitative trait loci

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(9), P. 1290 - 1299

Published: Sept. 1, 2021

Abstract Many gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals still not been identified. In the present study, we eQTL Catalogue ( https://www.ebi.ac.uk/eqtl ), resource of quality-controlled, uniformly re-computed splicing QTLs from 21 studies. We find that, matching cell types tissues, effect sizes highly reproducible Although were shared bulk identified greater diversity cell-type-specific purified types, subset also manifested new disease co-localizations. Our statistics freely available enable systematic interpretation GWAS associations across many tissues.

Language: Английский

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Graph representation learning in biomedicine and healthcare

Nature Biomedical Engineering, Journal Year: 2022, Volume and Issue: 6(12), P. 1353 - 1369

Published: Oct. 31, 2022

Language: Английский

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Systematic differences in discovery of genetic effects on gene expression and complex traits

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(11), P. 1866 - 1875

Published: Oct. 19, 2023

Language: Английский

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Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(3), P. 377 - 388

Published: Feb. 23, 2023

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples 14 brain datasets to create the MetaBrain resource and performed cis- trans-expression quantitative trait locus (eQTL) meta-analyses in multiple region- ancestry-specific (n ≤ 2,759). Many 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. inferred cell types for 3,549 by interaction analysis. prioritized 186 31 brain-related traits using Mendelian randomization co-localization including 40 an type, such as a neuron-specific cis-eQTL (CYP24A1) sclerosis. further describe 737 trans-eQTLs 526 unique variants 108 genes. used brain-specific gene-co-regulation networks link GWAS loci prioritize additional genes five central nervous system diseases. This study represents valuable post-GWAS research on

Language: Английский

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Single-cell eQTL models reveal dynamic T cell state dependence of disease loci

Nature, Journal Year: 2022, Volume and Issue: 606(7912), P. 120 - 128

Published: May 11, 2022

Language: Английский

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Human immune diversity: from evolution to modernity

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(12), P. 1479 - 1489

Published: Nov. 18, 2021

Language: Английский

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Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(6), P. 827 - 836

Published: June 1, 2022

Language: Английский

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From variant to function in human disease genetics

Science, Journal Year: 2021, Volume and Issue: 373(6562), P. 1464 - 1468

Published: Sept. 23, 2021

Over the next decade, primary challenge in human genetics will be to understand biological mechanisms by which genetic variants influence phenotypes, including disease risk. Although scale of this is daunting, better methods for functional variant interpretation have transformative consequences diagnosis, risk prediction, and development new therapies. An array characterizing impact at scale, using patient tissue samples as well vitro models, are already being applied dissect across a range cell types environments. These approaches also increasingly deployed clinical settings. We discuss rationale, approaches, applications, future outlook molecular cellular effects variants.

Language: Английский

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RNA editing underlies genetic risk of common inflammatory diseases

Nature, Journal Year: 2022, Volume and Issue: 608(7923), P. 569 - 577

Published: Aug. 3, 2022

Language: Английский

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