Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment DOI Creative Commons
Carina Seah, Anne Elizabeth Sidamon‐Eristoff, Laura M. Huckins

et al.

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(5)

Published: March 2, 2025

Exposure to traumatic stress is common in the general population. Variation brain's molecular encoding of potentially contributes heterogeneous clinical outcomes response experiences. For instance, only a minority those exposed trauma will develop post-traumatic disorder (PTSD). Risk for PTSD at least partially heritable, with growing number genetic factors identified through GWAS. A major limitation studies that they capture component risk, whereas by definition requires an environmental exposure. Furthermore, extent, timing, and type affects susceptibility. Here, we discuss mechanisms risk together gene × environment interactions, focus on how either might inform screening individuals high disease, reveal biological one day yield novel therapeutics, impact best practices even today. To close, interaction sex, gender, race, implications treatment. Altogether, suggest predicting, preventing, treating require integrating both genotypic information.

Language: Английский

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

313
Systematic differences in discovery of genetic effects on gene expression and complex traits DOI
Hakhamanesh Mostafavi, Jeffrey P. Spence,

Sahin Naqvi

et al.

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

Published: Oct. 19, 2023

Language: Английский

Citations

158
Predicting RNA splicing from DNA sequence using Pangolin DOI Creative Commons

Tony Zeng,

Yang Li

Genome biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: April 21, 2022

Abstract Recent progress in deep learning has greatly improved the prediction of RNA splicing from DNA sequence. Here, we present Pangolin, a model to predict splice site strength multiple tissues. Pangolin outperforms state-of-the-art methods for predicting on variety tasks. improves impact genetic variants splicing, including common, rare, and lineage-specific variation. In addition, identifies loss-of-function mutations with high accuracy recall, particularly that are not missense or nonsense, demonstrating remarkable potential identifying pathogenic variants.

Language: Английский

Citations

121
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

102
Limited overlap of eQTLs and GWAS hits due to systematic differences in discovery DOI Creative Commons
Hakhamanesh Mostafavi, Jeffrey P. Spence,

Sahin Naqvi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: May 8, 2022

Abstract Most signals in genome-wide association studies (GWAS) of complex traits point to noncoding genetic variants with putative gene regulatory effects. However, currently identified expression quantitative trait loci (eQTLs) explain only a small fraction GWAS signals. By analyzing hits for the UK Biobank, and cis-eQTLs from GTEx consortium, we show that these assays systematically discover different types genes variants: eQTLs cluster strongly near transcription start sites, while do not. Genes are enriched numerous functional annotations, under strong selective constraint have landscape across tissue/cell types, depleted most relaxed constraint, simpler landscapes. We describe model understand observations, including how natural selection on hinders discovery functionally-relevant eQTLs. Our results imply eQTL biased toward variants, support use complementary approaches alongside next generation studies.

Language: Английский

Citations

91
Molecular quantitative trait loci DOI
François Aguet, Kaur Alasoo, Yang Li

et al.

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

Published: Jan. 25, 2023

Language: Английский

Citations

52
Cell-type-specific and disease-associated expression quantitative trait loci in the human lung DOI Creative Commons
Heini M. Natri, Christina B. Azodi,

Lance Peter

et al.

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

Citations

23
Genetic and molecular architecture of complex traits DOI Creative Commons
Tuuli Lappalainen, Yang Li, Sohini Ramachandran

et al.

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

Published: Feb. 1, 2024

Language: Английский

Citations

21
Spatially resolved mapping of cells associated with human complex traits DOI Creative Commons

Liyang Song,

Wenhao Chen,

Junren Hou

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Depicting spatial distributions of disease-relevant cells is crucial for understanding disease pathology1,2. Here we present genetically informed mapping complex traits (gsMap), a method that integrates transcriptomics data with summary statistics from genome-wide association studies to map human traits, including diseases, in spatially resolved manner. Using embryonic datasets covering 25 organs, benchmarked gsMap through simulation and by corroborating known trait-associated or regions various organs. Applying brain data, reveal the distribution glutamatergic neurons associated schizophrenia more closely resembles cognitive than mood such as depression. The schizophrenia-associated were distributed near dorsal hippocampus, upregulated expression calcium signalling regulation genes, whereas depression-associated deep medial prefrontal cortex, neuroplasticity psychiatric drug target genes. Our study provides demonstrates gain biological insights (such trait-relevant related signature genes) these maps. Integration enables diseases other traits.

Language: Английский

Citations

2
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