Identification and characterization of gene regulatory variants in multifactorial diseases
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Philipps-Universität Marburg
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Abstract
Multifactorial diseases are characterized by the cumulative effect of multiple genetic risk factors. The vast majority of these risk factors represent gene regulatory variants that modulate the expression of genes. This thesis focuses on different approaches for the identification and characterization of gene regulatory variants with respect to diseases.
By analyzing the relationship between evolutionary conservation, expression level and genetic association in multifactorial diseases, we identified both higher-level correlations and phenotype-specific differences. The majority of genes associated with traits in the Genome-Wide Association Study ATLAS exhibited a positive correlation between genetic association and expression level. The correlation between genetic association and evolutionary rate, however, exhibited trait-specific differences. In particular, we found significantly higher evolutionary rates for genes associated with immunological traits compared to genes associated with metabolic traits. Notably, the expression level of trait-associated genes was consistent across different tissues and the evolutionary rate did not significantly change when compared with genes implicated in monogenic diseases. These results underline the smaller impact of low-expressed genes on the development of diseases and indicate differing selective pressures on multifactorial phenotypes. The observed relations between expression level and evolutionary conservation of genes might help in future to prioritize genetic variants and regulated genes as disease-relevant for multifactorial diseases.
In a second study, we analyzed the transcriptomic profile of two gastric regions, antrum and corpus, to evaluate the role of gene regulatory variants in gastric physiology as well as their contribution to pathophysiological processes. Expression analysis revealed a high number of differentially expressed genes with a significant overlap between both gastric sites. Enriched pathways showed functional characteristics that are related to epithelial renewal in antrum and to energy metabolism and gastric juice production in corpus. Furthermore, site-specific genes were regulated to a notable extent by expression quantitative trait loci and showed associations to cardiovascular, metabolic and obesity-related traits. Based on transcriptome-wide association studies we identified gene regulatory variants leading to a dysregulation of NQO1 in cataracts, MUC1 in gout and RAB27B in different weight-associated traits. Our study thus linked the transcriptomic profile and its regulation by genomic variants to multifactorial diseases. The results highlight the role of regulatory variants in defining functional differences across related tissues and underline the impact of these variants on pathophysiological processes.
To further consider the effect of exogenous stimuli on gene regulatory mechanisms in multifactorial diseases, we analyzed exposure expression quantitative trait loci in the context of DNA damage-induced apoptosis. Transcriptional profiling of CD8+ T cells treated with high doses of different carcinogens revealed a selective downregulation of transcription that was influenced by the type of DNA lesion. By analyzing expression quantitative trait loci, we identified 654 genes regulated by genomic variants. Among them, 61 % to 69 % were differentially expressed and 4 % to 5 % exhibited context specific effects. Due to the cell type and context specificity of our study, we found divergent effects of genomic variants compared to previous studies in whole blood under baseline conditions. By integrating regulatory variants with data from genome-wide association studies, we were able to identify associations with different oncological diseases. In particular, we found a context-specific regulation of XBP1 as risk factor for breast and ovarian cancer as well as of KLF2 as risk factor for multiple myeloma. These results underline the relevance of DNA damage-induced apoptosis for cancer pathophysiology and highlight the impact of inter-individual genetic variability on regulatory mechanisms in oncological diseases.
To conclude, the present studies on gene regulatory mechanisms contribute to the elucidation of the genetic architecture of multifactorial diseases. The results highlight the role of regulatory variants in pathophysiological processes and provide new targets for personalized prevention and treatment strategies.
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Dates
Created: 2024Issued: 2025-06-23Updated: 2025-06-23
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
eng
Data types
DoctoralThesis
Keywords
expression quantitative trait lociGenome-wide association studyEvolutionDNA Schadenexposure expression quantitative trait lociexpression quantitative trait locistomachGenom-weite AssoziationsstudieMagenapoptosisexposure expression quantitative trait locimultifactorial diseasesevolutionDNA damageApoptosemultifaktorielle Erkrankungen
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610
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Bigge, Jessica (0009-0006-3934-8102): Identification and characterization of gene regulatory variants in multifactorial diseases. : Philipps-Universität Marburg 2025-06-23. DOI: https://doi.org/10.17192/z2024.0356.
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This item has been published with the following license: In Copyright