Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116061 | GEO | 2018/06/21
REPOSITORIES: GEO
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Project description:Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.
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Project description:Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk
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Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive phosphoproteomic profiles of FLCN-POS and FLCN-NEG human tumor cells (UOK257). UOK257 misses the folliculin (FLCN) gene, whereas UOK 257-2 harbours a lentiviral rescue of the FLCN gene. Experiment performed in duplicate. This data set is linked to PXD021346 that describes phosphoproteomics results for human renal tubular epithelial cells (RPTEC/TERT1).
2022-07-11 | PXD030237 | Pride
Project description:Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10-7). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.
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Project description:Birt-Hogg-Dube (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells with short-term and long-term folliculin (FLCN) knockdown. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G1/S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). Taken together with our proteomic work, our findings indicate that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.
2024-11-28 | GSE283021 | GEO
Project description:The Folliculin-Fnip1 pathway deleted in human Birt-Hogg-Dube syndrome is required for B cell development.
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Project description:Characterizing the tumor suppressor activity of FLCN in Birt-Hogg-Dube syndrome through transcriptiomic and proteomic analysis
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Project description:BackgroundGenomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC.MethodsThe population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases.ResultsA linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC.ConclusionsThis study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC.ImpactOur results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
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Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
2023-02-12 | GSE218784 | GEO
Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
2023-02-12 | GSE209898 | GEO