DNA methylation QTL mapping across diverse human tissues provides molecular links between genetic variation and complex traits

Nature Genetics, Journal Year: 2022, Volume and Issue: 55(1), P. 112 - 122

Published: Dec. 12, 2022

Language: Английский

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The missing link between genetic association and regulatory function

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

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A compendium of genetic regulatory effects across pig tissues

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(1), P. 112 - 123

Published: Jan. 1, 2024

Abstract The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking polymorphisms variation phenotypes, helping fundamental biological discovery and exploitation animal breeding human biomedicine. Here we show results from the pilot phase PigGTEx by processing 5,457 RNA-sequencing 1,602 whole-genome sequencing samples passing quality control pigs. We build pig genotype imputation panel associate millions with five types transcriptomic phenotypes 34 tissues. evaluate tissue specificity effects elucidate molecular mechanisms their action using multi-omics data. Leveraging this resource, decipher underlying 207 complex demonstrate similarity pigs humans gene expression regulation behind supporting importance as biomedical model.

Language: Английский

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Single-cell genomics meets human genetics

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(8), P. 535 - 549

Published: April 21, 2023

Language: Английский

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Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Science, Journal Year: 2023, Volume and Issue: 380(6643)

Published: April 27, 2023

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability discern which positions functionally important. Evolutionary constraint is a powerful predictor function, agnostic cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% the genome as significantly constrained and likely functional. We compared annotation, association studies, copy-number variation, clinical genetics findings, cancer data. Constrained enriched for variants that explain common heritability more than other functional annotations. Our results improve variant annotation also highlight regulatory landscape still needs be further explored linked disease.

Language: Английский

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Molecular quantitative trait loci

Nature Reviews Methods Primers, Journal Year: 2023, Volume and Issue: 3(1)

Published: Jan. 25, 2023

Language: Английский

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Hold out the genome: a roadmap to solving the cis-regulatory code

Nature, Journal Year: 2023, Volume and Issue: 625(7993), P. 41 - 50

Published: Dec. 13, 2023

Language: Английский

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Cell-type-specific and disease-associated expression quantitative trait loci in the human lung

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(4), P. 595 - 604

Published: March 28, 2024

Abstract Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis. Defining the control of gene expression in a cell-type-specific and context-dependent manner is critical understanding mechanisms through which variation influences complex traits disease pathobiology. To this end, we performed single-cell RNA sequencing tissue from 66 individuals with fibrosis 48 unaffected donors. Using pseudobulk approach, mapped quantitative trait loci (eQTLs) across 38 cell types, observing both shared regulatory effects. Furthermore, identified interaction eQTLs demonstrated that class associations more likely to be linked cellular dysregulation Finally, connected their targets disease-relevant types. These results indicate context determines impact on implicates context-specific as key regulators homeostasis disease.

Language: Английский

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Genetic and molecular architecture of complex traits

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1059 - 1075

Published: Feb. 1, 2024

Language: Английский

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Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

Science, Journal Year: 2024, Volume and Issue: 384(6698)

Published: May 23, 2024

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment regulatory elements in the developing brain. However, prioritizing risk genes mechanisms is challenging without a unified atlas. Across 672 diverse human brains, we identified 15,752 harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing heterogeneity intrinsic properties of neuronal maturation. Isoform-level regulation, particularly second trimester, mediated largest proportion GWAS heritability. Through colocalization, prioritized about 60% loci across five disorders, exceeding adult brain findings. Finally, contextualized results within gene isoform coexpression networks, revealing comprehensive landscape transcriptome regulation development disease.

Language: Английский

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