scholarly journals Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Christelle Adolphe ◽  
Angli Xue ◽  
Atefeh Taherian Fard ◽  
Laura A. Genovesi ◽  
Jian Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Network Analysis ◽  
Basal Cell Carcinoma ◽  
Regulatory Network ◽  
Interaction Network ◽  
Susceptibility Genes ◽  
Genome Wide Association ◽  
Functional Interaction ◽  
Functional Interaction Network ◽  
Genome Wide

Abstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or which modulate the tumour microenvironment or host immune system play significant roles in determining whether genetic mutations culminate in BCC development. We set out to define background genetic factors that play a role in influencing BCC susceptibility via promoting or suppressing the effects of oncogenic drivers of BCC. Methods We performed genome-wide association studies (GWAS) on 17,416 cases and 375,455 controls. We subsequently performed statistical analysis by integrating data from population-based genetic studies of multi-omics data, including blood- and skin-specific expression quantitative trait loci and methylation quantitative trait loci, thereby defining a list of functionally relevant candidate BCC susceptibility genes from our GWAS loci. We also constructed a local GWAS functional interaction network (consisting of GWAS nearest genes) and another functional interaction network, consisting specifically of candidate BCC susceptibility genes. Results A total of 71 GWAS loci and 46 functional candidate BCC susceptibility genes were identified. Increased risk of BCC was associated with the decreased expression of 26 susceptibility genes and increased expression of 20 susceptibility genes. Pathway analysis of the functional candidate gene regulatory network revealed strong enrichment for cell cycle, cell death, and immune regulation processes, with a global enrichment of genes and proteins linked to TReg cell biology. Conclusions Our genome-wide association analyses and functional interaction network analysis reveal an enrichment of risk variants that function in an immunosuppressive regulatory network, likely hindering cancer immune surveillance and effective antitumour immunity.

Genome-Wide Association Scan for Type 1 Diabetes Susceptibility Genes in a Danish Population

2007 ◽  
Vol 123 ◽  
pp. S23-S24
Author(s):  
Caroline Brorsson ◽  
Elzbieta Swiergala ◽  
Kristoffer Rapacki ◽  
Regine Bergholdt ◽  
Shaun Purcell ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Susceptibility Genes ◽  
Genome Wide Association ◽  
Danish Population ◽  
Diabetes Susceptibility ◽  
Genome Wide

Abstract MP208: A Shared Fog2 / Tbx5-dependent Gene Regulatory Network Identified By Transcription Factor-dependent Non-coding RNA Profiling Modulates Cardiac Rhythm

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Linsin A Smith ◽  
Carlos Perez-Cervantes ◽  
Michael Broman ◽  
Rangarajan Nadadur ◽  
Jeff Steimle ◽  
...  
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Cardiac Rhythm ◽  
Association Studies ◽  
Genome Wide Association ◽  
Calcium Handling ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Gene Regulatory ◽  
Atrial Rhythm

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over 33 million individuals throughout the world. AF is highly heritable and recent genome-wide association studies (GWAS) have cumulatively identified over 100 loci associated with AF risk. Genome-wide association studies (GWAS) often identify transcription factor (TF) loci in association with complex human diseases, implying that a significant transcriptional component underlies human disease risk and etiology. The transcription factors ZFPM2 (FOG2), GATA4, and TBX5 have all been implicated in human AF risk by genetic studies. We hypothesized that FOG2, GATA4, and TBX5 functionally interact to regulate a gene regulatory network essential for atrial rhythm control. We generated a novel mouse model of spontaneous AF based on FOG2 overexpression. FOG2 ChIP-seq identified FOG2 genomic localization at loci co-occupied by GATA4, a known FOG2 binding partner. However, we found that FOG2 OE caused gene expression alterations that correlated more highly with TBX5-dependent rather than GATA4-dependent gene expression, including a module of calcium handling genes required for atrial rhythm homeostasis. We applied TF-dependent non-coding transcriptional profiling to examine the FOG2 dependent atrial GRN, which identified 805 candidate regulatory regions with accessible chromatin and FOG2 dependent ncRNAs. TBX5 removal and FOG2 OE caused highly correlated dysregulation of ncRNA expression at open chromatin regions genome-wide, suggesting a functional interaction between TBX5 and FOG2. Furthermore, FOG2 OE only affected enhancer activity by altered ncRNA abundance at locations of TBX5 co-binding. The shared TBX5/FOG2 genomic interaction predicted a potential genetic interaction, and we found that cardiac rhythm abnormalities caused by Tbx5 haploinsufficiency were rescued by Fog2 haploinsufficiency. Taken together, TF-dependent ncRNA-profiling revealed an interconnected cardiac rhythm gene regulatory network (GRN) between FOG2, TBX5 and GATA4. These data nominate a specific model in which FOG2 is recruited by GATA4 to modulate a co-bound TBX5-dependent atrial gene regulatory network for calcium handling and atrial rhythm homeostasis.

scholarly journals Pathway-Wide Genetic Risks in Chlamydial Infections Overlap between Tissue Tropisms: A Genome-Wide Association Scan

2018 ◽  
Vol 2018 ◽  
pp. 1-9
Author(s):  
Chrissy H. Roberts ◽  
Sander Ouburg ◽  
Mark D. Preston ◽  
Henry J. C. de Vries ◽  
Martin J. Holland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chlamydia Trachomatis ◽  
Mitotic Cell ◽  
Genome Wide Association ◽  
Serological Response ◽  
Transmitted Infection ◽  
Genome Wide ◽  
A Genome ◽  
Tissue Tropisms ◽  
Chlamydial Infections

Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein-coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle, and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case-control study, we performed genome-wide association and pathways-based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high-risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway-level associations appear to be common to immunological sequelae of chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases.

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