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

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases DOI
Jie Zheng, Valeriia Haberland, Denis Baird

et al.

Nature Genetics, Journal Year: 2020, Volume and Issue: 52(10), P. 1122 - 1131

Published: Sept. 7, 2020

Language: Английский

Citations

574
Cell type–specific genetic regulation of gene expression across human tissues DOI Open Access
Sarah Kim-Hellmuth, François Aguet, Meritxell Oliva

et al.

Science, Journal Year: 2020, Volume and Issue: 369(6509)

Published: Sept. 10, 2020

Cell type composition, estimated from bulk tissue, maps the cellular specificity of genetic variants.

Language: Английский

Citations

486
Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response DOI
Kaur Alasoo,

Julia Rodrigues,

Subhankar Mukhopadhyay

et al.

Nature Genetics, Journal Year: 2018, Volume and Issue: 50(3), P. 424 - 431

Published: Jan. 29, 2018

Language: Английский

Citations

319
A compendium of uniformly processed human gene expression and splicing quantitative trait loci DOI Creative Commons
Nurlan Kerimov, James Hayhurst,

Kateryna Peikova

et al.

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

Citations

312
The role of sex in the genomics of human complex traits DOI
Ekaterina Khramtsova, Lea K. Davis, Barbara E. Stranger

et al.

Nature Reviews Genetics, Journal Year: 2018, Volume and Issue: 20(3), P. 173 - 190

Published: Dec. 23, 2018

Language: Английский

Citations

269
Landscape of stimulation-responsive chromatin across diverse human immune cells DOI
Diego Calderon,

Michelle Nguyen,

Anja Mezger

et al.

Nature Genetics, Journal Year: 2019, Volume and Issue: 51(10), P. 1494 - 1505

Published: Sept. 30, 2019

Language: Английский

Citations

260
Where Are the Disease-Associated eQTLs? DOI
Benjamin D. Umans, Alexis Battle, Yoav Gilad

et al.

Trends in Genetics, Journal Year: 2020, Volume and Issue: 37(2), P. 109 - 124

Published: Sept. 7, 2020

Language: Английский

Citations

255
Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges DOI Creative Commons

Barbara Piasecka,

Darragh Duffy, Alejandra Urrutia

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 115(3)

Published: Dec. 27, 2017

Significance Identifying the drivers of interindividual diversity human immune system is crucial to understand their consequences on immune-mediated diseases. By examining transcriptional responses 1,000 individuals various microbial challenges, we show that age and sex influence expression many immune-related genes, but effects are overall moderate, whereas genetic factors affect a smaller gene set with stronger effect. We identify numerous variants variation infection, which associated autoimmune or inflammatory disorders. These results enable additional exploration role regulatory in pathogenesis diseases improve our understanding respective age, sex, genetics response variation.

Language: Английский

Citations

205
The missing link between genetic association and regulatory function DOI Creative Commons
Noah J Connally,

Sumaiya Nazeen,

Daniel Lee

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Dec. 14, 2022

The genetic basis of most traits is highly polygenic and dominated by non-coding alleles. It widely assumed that such alleles exert small regulatory effects on the expression cis -linked genes. However, despite availability gene epigenomic datasets, few variant-to-gene links have emerged. unclear whether these sparse results are due to limitations in available data methods, or deficiencies underlying model. To better distinguish between possibilities, we identified 220 gene–trait pairs which protein-coding variants influence a complex trait its Mendelian cognate. Despite presence quantitative loci near GWAS associations, applying gene-based approach found limited evidence baseline trait-related genes explains using colocalization methods (8% implicated), transcription-wide association (2% combination annotations distance (4% implicated). These contradict hypothesis trait-associated coincide with homeostatic QTLs, suggesting models needed. field must confront this deficit pursue ‘missing regulation.’

Language: Английский

Citations

100
Human Immunology through the Lens of Evolutionary Genetics DOI Creative Commons
Lluís Quintana‐Murci

Cell, Journal Year: 2019, Volume and Issue: 177(1), P. 184 - 199

Published: March 1, 2019

Language: Английский

Citations

145