Integrating GWAS and eQTL to predict genes and pathways for non‐syndromic cleft lip with or without palate

Yang, Jing; Yu, Xin; Zhu, Guirong; Wang, Ruimin; Lou, Shu; Zhu, Weihao; Fu, Chengyi; Liu, Jinsuo; Fan, Liwen; Li, Dandan; Shao, Qiyue; Ma, Lan; Wang, Lin; Wang, Zhendong; Pan, Yongchu

doi:10.1111/odi.13699

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…We found that many of the genes with increased expression in the hypertrophic region of dorsal lip were already demonstrated to play a role in lip morphogensis and pathobiology in other vertebrates, including alx1 [32], alx3 [33], angptl2 [34], arid3a [35], crip2 [36], ddr2 [37], dpysl2 [38], itga5 [39], lmna [40], mgp [41], rgs5 [42], rhob [42,43], rxfp2 [44], sostdc1 [42,45], thbs3 [46], vcan [47,48], and vtn [49]. Among the transcriptionally repressed genes, we also found candidates with functions which were previously implicated in defective lip morphogenesis in other vertebarates such as cd96 [50], ep300 [51][52], fgfrl1 [53], frzb [54], hectd1 [55,56], mmp13 [49], slc16a6 [57], and syne1 [58].…”

Section: Discussionmentioning

confidence: 84%

Transcriptomics Unravels Molecular Players Shaping Dorsal Lip Hypertrophy in the Vacuum Cleaner Cichlid, Gnathochromis Permaxillaris

Lecaudey

Singh

Sturmbauer

et al. 2021

Preprint

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Background:Teleosts display a spectacular diversity of craniofacial adaptations that often mediate ecological specializations. A considerable amount of research has revealed molecular players underlying skeletal craniofacial morphologies, but less is known about soft craniofacial phenotypes. Here we focus on a bizarre example of lip hypertrophy in the Lake Tangnayika cichlid, Gnathochromis permaxillaris, that is considered to be a dietary adaptation to suck invertebrates out of narrow crevices. In this study, we investigate the molecular and regulatory basis of lip development G. permaxillaris, using a comparative transcriptomic approach.Results: We identified a gene regulatory network involved in tissue overgrowth and cellular hypertrophy, potentially associated with the formation of a locally restricted hypertrophic lip in a teleost fish species. Of particular interest were the increased expression level of apoda and fhl2, as well as reduced expression of cyp1a, gimap8, lama5 and rasal3, in the hypertrophic lip region which have been implicated in formation of lip structure in other vertebrates. Among the predicted upstream transcription factors, we found reduced expression foxp1 in the hypertrophic lip region, which is known to act as repressor of cell growth and proliferation and its function has been associated with hypertrophy of upper lip in human. Conclusion: Our results provide a genetic foundation for future studies of molecular players shaping soft and exaggerated, but locally restricted, craniofacial morphological changes in fish and perhaps across vertebrates.

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Section: Discussionmentioning

confidence: 84%

Transcriptomics Unravels Molecular Players Shaping Dorsal Lip Hypertrophy in the Vacuum Cleaner Cichlid, Gnathochromis Permaxillaris

Lecaudey

Singh

Sturmbauer

et al. 2021

Preprint

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“…They demonstrated that NSCL/P development could be regulated by genes related to ubiquitin-mediated proteolysis and DNA synthesis, and the fatty acid metabolism pathway. 23 Deubiquitination, described as the removal of ubiquitin from the protein substrate bound by ubiquitin, is mediated by several deubiquitinating enzymes (DUBs), including ubiquitin-specific processing protease (USP). 24 USP17L6P belongs to a subfamily of cytokine-inducible DUBs.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Molecular Mechanism of lncRNA–miRNA–mRNA Networks in Non-Syndromic Cleft Lip with or without Cleft Palate

Wang¹,

Guo²,

Zhou³

et al. 2021

IJGM

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Background Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common craniofacial birth defect. Growing evidence has demonstrated the competing endogenous RNA (ceRNA) hypothesis has played a role in the pathogenesis of NSCL/P. Here, we identified the important lncRNAs in NSCL/P and constructed a ceRNA regulatory network to predict their underlying functional mechanism. Methods Total RNA isolated from the peripheral blood samples were analyzed by the Human Clariom D Affymetrix platform and differentially expressed genes (DEGs) were identified. Using the limma package in R software, DEGs in the expression profile of GSE42589 were identified from Gene Expression Omnibus (GEO) database. Co-differentially expressed lncRNAs (co-DElncRNAs) were used to predict the microRNAs that may bind to them. Co-differentially expressed mRNAs (co-DEmRNAs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The hub genes were screened using the cytohubba plug-in in Cytoscape. A ceRNA network was built to investigate the molecular mechanism underlying the etiology of NSCL/P. The expression levels of lncRNAs, miRNAs, and mRNAs in the network were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Results We found 116 DElncRNAs and 2955 DEmRNAs from the GSE42589 dataset, and 2626 DElncRNAs and 2771 DEmRNAs from the Human Clariom D gene chip. A network of co-DEmRNAs containing 3712 edges and 621 nodes were identified by PPI analysis. A ceRNA regulatory network comprising lncRNA USP17L6P, hsa-miR-449c-5p, and MYC was established. qRT-PCR results revealed significantly lower expression levels of lncRNA USP17L6P and c-Myc in NSCL/P tissues, while the expression level of hsa-miR-449c-5p was higher as compared to control samples ( p < 0.05). Conclusion The identified lncRNAs and the established ceRNA regulatory network provide novel insight into the pathogenesis of NSCL/P, therefore hold great promise in NSCL/P management in clinical practice.

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“…The whole-blood eQTL data was derived from the Genotype-Tissue Expression (GTEx) version 6 database (n = 338) [ 17 ]. The gene expression data was obtained using paired-end RNA-seq (Illumina TruSeq; Illumina Inc) and the genotype data was from whole-genome sequencing.…”

Section: Methodsmentioning

confidence: 99%

Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood

Chen

Huang

et al. 2022

J Transl Med

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Background Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes. Methods Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood. Results Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes. Conclusions Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies.

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Integrating GWAS and eQTL to predict genes and pathways for non‐syndromic cleft lip with or without palate

Cited by 14 publications

References 38 publications

Transcriptomics Unravels Molecular Players Shaping Dorsal Lip Hypertrophy in the Vacuum Cleaner Cichlid, Gnathochromis Permaxillaris

Transcriptomics Unravels Molecular Players Shaping Dorsal Lip Hypertrophy in the Vacuum Cleaner Cichlid, Gnathochromis Permaxillaris

Exploring the Molecular Mechanism of lncRNA–miRNA–mRNA Networks in Non-Syndromic Cleft Lip with or without Cleft Palate

Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood

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