Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes DOI Creative Commons
Tongwu Zhang, Jiyeon Choi, Michael A. Kovacs

et al.

Genome Research, Journal Year: 2018, Volume and Issue: 28(11), P. 1621 - 1635

Published: Oct. 17, 2018

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise melanoma but account for <5% typical skin biopsies, we an eQTL analysis primary melanocyte cultures from 106 newborn males. We identified 597,335 cis -eQTL SNPs prior linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably those 44 GTEx tissue types, including skin. Over a third eGenes, key genes melanin synthesis pathways, were unique melanocytes compared or TCGA melanomas. The data set also trans -eQTLs, connecting pigmentation-associated functional SNP with four genes, likely through -regulation IRF4 . are enriched -regulatory signatures found well melanoma-associated variants genome-wide association studies. colocalized GWAS five known loci. Finally, transcriptome-wide study using uncovered novel susceptibility loci, where imputed levels ( ZFP90 , HEBP1 MSC CBWD1 RP11-383H13.1 ) associated at significant P -values. Our highlight utility lineage-specific resources annotating findings, present robust database genomic research risk biology.

Language: Английский

The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes DOI
Mireia Ramos-Rodríguez, Helena Raurell‐Vila, Máikel L. Colli

et al.

Nature Genetics, Journal Year: 2019, Volume and Issue: 51(11), P. 1588 - 1595

Published: Nov. 1, 2019

Language: Английский

Citations

136
Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation DOI Creative Commons
Lucas Husquin, Maxime Rotival, Maud Fagny

et al.

Genome biology, Journal Year: 2018, Volume and Issue: 19(1)

Published: Dec. 1, 2018

DNA methylation is influenced by both environmental and genetic factors increasingly thought to affect variation in complex traits diseases. Yet, the extent of ancestry-related differences methylation, their determinants, respective causal impact on immune gene regulation remain elusive. We report extensive population between 156 individuals African European descent, detected primary monocytes that are used as a model major innate immunity cell type. Most these (~ 70%) driven sequence variants nearby CpG sites, which account for ~ 60% variance methylation. also identify several master regulators trans, including regulatory hub transcription factor-encoding CTCF gene, contributes markedly Furthermore, we establish associated with varying expression levels following mostly, but not exclusively, canonical negative associations, particularly enhancer regions. Specifically, find highly correlates transcriptional activity 811 230 genes, at basal state upon stimulation, respectively. Finally, using Bayesian approach, estimate mediation effects 20% studied cases, indicating can play an active role regulation. Using system-level our study reveals substantial provides evidence

Language: Английский

Citations

116
Enterovirus and Encephalitis DOI Creative Commons

Bo‐Shiun Chen,

Hou-Chen Lee,

Kuo-Ming Lee

et al.

Frontiers in Microbiology, Journal Year: 2020, Volume and Issue: 11

Published: Feb. 20, 2020

Enterovirus-induced infection of the central nervous system (CNS) results in acute inflammation brain (encephalitis) and constitutes a significant global burden to human health. These viruses are thought be highly cytolytic, therefore normal function could greatly compromised following enteroviral CNS. A further layer complexity is added by evidence showing that some enteroviruses may establish persistent within CNS eventually lead pathogenesis certain neurodegenerative disorders. Interestingly, enterovirus encephalitis particularly common among young children, suggesting potential causal link between development neuroimmune neuroinvasion. Although involvement infections relatively rare complication, it represents serious underlying cause mortality. Here we review selection infect discuss recent advances characterization these with regard their routes infection, tropism, virulence immune responses.

Language: Английский

Citations

96
Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk DOI Creative Commons
Derviş A. Salih, Sevinç Bayram, Sebastian Guelfi

et al.

Brain Communications, Journal Year: 2019, Volume and Issue: 1(1)

Published: Jan. 1, 2019

Abstract Genome-wide association studies of late-onset Alzheimer’s disease risk have previously identified genes primarily expressed in microglia that form a transcriptional network. Using transgenic mouse models amyloid deposition, we showed many the orthologues these are co-expressed and associated with pathology. In this new study, generate an improved RNA-seq-derived network is amyloid-responsive statistically compare gene-level variation previous human genome-wide to predict at least four for (OAS1, LAPTM5, ITGAM/CD11b LILRB4). Of Oas1a likely respond directly level, similarly established gene Trem2, because increase Trem2 transcripts response deposition mice significantly higher than both average microglial transcript number. contrast, LILRB4 (Laptm5, Itgam/CD11b Lilra5) show increased presence plaques similar magnitude number, except Laptm5 Lilra5 quicker as plaque load becomes dense. This work suggests genetic variability major determinant risk, identification may help developing disease. These findings also provide further insights into mechanisms underlying potential drug discovery.

Language: Английский

Citations

93
A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene DOI Creative Commons
Naciye Magusali, Andrew Graham, Thomas M. Piers

et al.

Brain, Journal Year: 2021, Volume and Issue: 144(12), P. 3727 - 3741

Published: Sept. 11, 2021

Abstract Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed microglia. However, function OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic disease and 1234 control individuals, confirm variant, rs1131454, is associated increased for disease. The same locus has been recently severe coronavirus 2019 (COVID-19) outcomes, linking both diseases. single nucleotide polymorphisms rs1131454(A) rs4766676(T) are rs10735079(A) rs6489867(T) COVID-19, where alleles linked decreased expression. Analysing single-cell RNA-sequencing data myeloid cells COVID-19 patients, identify co-expression containing interferon (IFN)-responsive genes, including OAS1, which significantly upregulated age In human induced pluripotent stem cell-derived lowered expression, show exaggerated production TNF-α IFN-γ stimulation, indicating required limit pro-inflammatory response cells. Collectively, our support a link between genetic susceptibility critical illness centred on finding potential implications future treatments development biomarkers track progression.

Language: Английский

Citations

88
The impact of cell type and context-dependent regulatory variants on human immune traits DOI Creative Commons
Zepeng Mu, Wei Wei, Benjamin Fair

et al.

Genome biology, Journal Year: 2021, Volume and Issue: 22(1)

Published: April 29, 2021

Abstract Background The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the loci unexplained by regulatory quantitative trait (QTLs). Results We perform a comprehensive characterization putative mechanisms which GWAS human immune traits. By harmonizing four major QTL studies, we identify 26,271 expression QTLs (eQTLs) 23,121 splicing (sQTLs) spanning 18 cell types. Our colocalization analyses between from 72 reveals that genetic effects on RNA in cells colocalize with 40.4% for immune-related traits, many cases increasing fraction colocalized two fold compared previous studies. Notably, find largest contributors this increase QTLs, average 14% all do not eQTLs. contrast, type-specific eQTLs, eQTLs small effect sizes contribute very few new colocalizations. To investigate 60% remain unexplained, collect H3K27ac CUT&Tag data rheumatoid arthritis healthy controls, large-scale differences different disease contexts, including at regions overlapping loci. Conclusion Altogether, our work supports as an important mediator suggests must expand study processes contexts improve functional interpretation yet

Language: Английский

Citations

59
Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions DOI Creative Commons
Anthony S Findley, Alan Monziani, Allison L. Richards

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: May 14, 2021

Genetic effects on gene expression and splicing can be modulated by cellular environmental factors; yet interactions between genotypes, cell type, treatment have not been comprehensively studied together. We used an induced pluripotent stem system to study multiple types derived from the same individuals exposed them a large panel of treatments. Cellular responses involved different genes pathways for were highly variable across contexts. For thousands genes, we identified allelic contexts characterized gene-environment interactions, many which are associated with complex traits. Promoter functional evolutionary features distinguished elevated imbalance mean variance. On average, half dynamic regulatory missed eQTL mapping studies, indicating importance exploring treatments reveal previously unrecognized loci that may important disease.The activity in depends type they in, other environment genetics. Active produce greater number mRNA molecules, act as messenger molecules instruct proteins. The amount cells measured assess levels activity. Genes mRNAs through process called transcription, collection all is transcriptome. Cells obtained human samples grown lab under conditions, this transform into cells. These then – such specific chemicals understand how affects them. people respond differently based their unique Exposing help explain genetics, affect Findley et al. grew three six lab. 28 treatments, reflect changes. Studying these factors together allowed over 53,000 genes. Around due interaction genetics had seen larger studies Many newly observed changes connections diseases, including heart disease. results provide evidence extent lifestyle interact individual’s genetic makeup impact long-term health. more researchers factors, useful helping predict, detect treat illnesses. findings also show interact, relevant understanding disease development. There work done wider range types. It will establish translates

Language: Английский

Citations

59
Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for 12 immune-mediated diseases DOI
Kousik Kundu, Manuel Tardáguila, Alice Mann

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(3), P. 251 - 262

Published: March 1, 2022

Language: Английский

Citations

44
Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes DOI Open Access
Rédouane Aherrahrou,

Dillon Lue,

R. Noah Perry

et al.

Circulation Research, Journal Year: 2023, Volume and Issue: 132(3), P. 323 - 338

Published: Jan. 4, 2023

Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses genome-wide association studies have identified over 175 loci associated with CAD. The majority these are in noncoding regions and predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles development progression CAD, we aimed identify subset CAD regulation transcription distinct SMC phenotypes.

Language: Английский

Citations

31
Methods and Insights from Single-Cell Expression Quantitative Trait Loci DOI Creative Commons

Joyce B. Kang,

Alessandro Raveane, Aparna Nathan

et al.

Annual Review of Genomics and Human Genetics, Journal Year: 2023, Volume and Issue: 24(1), P. 277 - 303

Published: May 17, 2023

Recent advancements in single-cell technologies have enabled expression quantitative trait locus (eQTL) analysis across many individuals at resolution. Compared with bulk RNA sequencing, which averages gene cell types and states, assays capture the transcriptional states of individual cells, including fine-grained, transient, difficult-to-isolate populations unprecedented scale Single-cell eQTL (sc-eQTL) mapping can identify context-dependent eQTLs that vary some colocalize disease variants identified genome-wide association studies. By uncovering precise contexts these act, approaches unveil previously hidden regulatory effects pinpoint important underlying molecular mechanisms disease. Here, we present an overview recently deployed experimental designs sc-eQTL In process, consider influence study design choices such as cohort, ex vivo perturbations. We then discuss current methodologies, modeling approaches, technical challenges well future opportunities applications.

Language: Английский

Citations

26