An integrated approach to identify environmental modulators of genetic risk factors for complex traits

Abstract Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental e...

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Vydáno v:bioRxiv
Hlavní autoři: Balliu, Brunilda, Ivan Carcamo -Orive, Gloudemans, Michael J, Nachun, Daniel C, Durrant, Matthew G, Gazal, Steven, Park, Chong Y, Knowles, David A, Wabitsch, Martin, Quertermous, Thomas, Knowles, Joshua W, Montgomery, Stephen B
Médium: Paper
Jazyk:angličtina
Vydáno: Cold Spring Harbor Cold Spring Harbor Laboratory Press 25.02.2021
Cold Spring Harbor Laboratory
Vydání:1.1
Témata:
Cell lines
Disease
Environmental effects
Genetic diversity
Genomics
Hepatocytes
Heritability
Homeostasis
Insulin
Insulin resistance
Phenotypes
Polygenic inheritance
Risk factors
Skeletal muscle
Transcription
Co-localization
GWAS
Gene expression
Gene-by-environment interactions
ISSN:2692-8205, 2692-8205
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Popis
Shrnutí:Abstract Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental exposures. We propose a novel framework for leveraging signals from transcriptional responses to environmental perturbations to identify disease-relevant perturbations that can modulate genetic risk for complex traits and inform the functions of genetic variants associated with complex traits. We perturbed human skeletal muscle, fat, and liver relevant cell lines with 21 perturbations affecting insulin resistance, glucose homeostasis, and metabolic regulation in humans and identified thousands of environmentally responsive genes. By combining these data with GWAS from 31 distinct polygenic traits, we show that heritability of multiple traits is enriched in regions surrounding genes responsive to specific perturbations and, further, that environmentally responsive genes are enriched for associations with specific diseases and phenotypes from the GWAS catalogue. Overall, we demonstrate the advantages of large-scale characterization of transcriptional changes in diversely stimulated and pathologically relevant cells to identify disease-relevant perturbations. Competing Interest Statement SBM is on the SAB for Myome.
Bibliografie:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
Competing Interest Statement: SBM is on the SAB for Myome.
ISSN:2692-8205
2692-8205
DOI:10.1101/2021.02.23.432608