scholarly journals Genetic variants in RET, ARHGEF3 and CTNNAL1, and relevant interaction networks, contribute to the risk of Hirschsprung disease

Aging ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 4379-4393 ◽  
Author(s):  
Yang Wang ◽  
Qian Jiang ◽  
Hao Cai ◽  
Ze Xu ◽  
Wenjie Wu ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hirschsprung Disease ◽  
Interaction Networks ◽  
Relevant Interaction

scholarly journals Contribution of Common Variants in GABRG2, RELN and NRG3 and Interaction Networks to the Risk of Hirschsprung Disease

2016 ◽  
Vol 40 (3-4) ◽  
pp. 509-526 ◽  
Author(s):  
Yang Wang ◽  
Jun Wang ◽  
Ying Zhou ◽  
Zhiyun Wei ◽  
Yongtao Xiao ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Interaction Analysis ◽  
Hirschsprung Disease ◽  
Gene Interaction ◽  
Han Chinese ◽  
Interaction Networks ◽  
Common Variants ◽  
Chinese Origin ◽  
Ptch1 Gene ◽  
Normal Controls

Background: Hirschsprung disease (HSCR) is a complex and heterogeneous disorder, characterized by a deficit in enteric nervous system. Genome-wide studies implied GABRG2, RELN and NRG3 might be involved in HSCR etiology. Here, we aimed to assess genetic variants in GABRG2, RELN and NRG3 that may confer susceptibility to HSCR and explore genetic interaction networks in HSCR. Methods: Using a strategy that combined case-control study and gene-gene interaction analysis with the MassArray system, we evaluated 24 polymorphisms within GABRG2, RELN and NRG3 in 104 HSCR cases and 151 normal controls of Han Chinese origin. Results: We observed that seven polymorphisms showed statistically significant differences between HSCR subjects and normal controls. For each of the three genes, the haplotypes which combined eight markers were the most significant. Moreover, we recruited SNPsyn, GO enrichment and MDR analyses to interrogate the interactions among GABRG2, RELN, NRG3 and our previous identified PTCH1 gene. Significant interaction networks were found among GABRG2, RELN, and PTCH1. Conclusion: We provide a first indication that common variants of GABRG2, RELN and NRG3 and the GABRG2-RELN-PTCH1 interaction networks might confer altered susceptibility to HSCR in the Han Chinese population, suggesting a potential mechanism underlying HSCR pathogenesis.

Genetic variants ofIL-11associated with risk of Hirschsprung disease

2015 ◽  
Vol 27 (10) ◽  
pp. 1371-1377 ◽  
Author(s):  
L. H. Kim ◽  
H. S. Cheong ◽  
J.-G. Shin ◽  
J.-M. Seo ◽  
D.-Y. Kim ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hirschsprung Disease

scholarly journals Whole-genome analysis of noncoding genetic variations identifies multigranular regulatory element perturbations associated with Hirschsprung disease

2020 ◽  
Author(s):  
Alexander Xi Fu ◽  
Kathy Nga-Chu Lui ◽  
Clara Sze-Man Tang ◽  
Ray Kit Ng ◽  
Frank Pui-Ling Lai ◽  
...  
Keyword(s):  
Neural Crest ◽  
Genetic Variants ◽  
Regulatory Element ◽  
Hirschsprung Disease ◽  
Regulatory Elements ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Whole Genome Analysis ◽  
Cell Stage

AbstractIt is widely recognized that the missing heritability of many human diseases is partially due to noncoding genetic variants, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals, and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multi-granular information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell-stage-specific regulatory roles three top novel regulatory elements on our list, respectively in the RET, RASGEF1A and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the affects the binding of the gliogenesis regulator NFIA, with a corresponding down-regulation of multiple genes in the same topologically associating domain.

scholarly journals The extracellular matrix phenome across species

2020 ◽  
Author(s):  
Cyril Statzer ◽  
Collin Y. Ewald
Keyword(s):  
Extracellular Matrix ◽  
Sonic Hedgehog ◽  
Genetic Variants ◽  
Association Studies ◽  
Interaction Networks ◽  
List Type ◽  
C Elegans ◽  
Age Related ◽  
Genome Wide ◽  
Molecular Components

AbstractExtracellular matrices are essential for cellular and organismal function. Recent genome-wide and phenome-wide association studies started to reveal a broad spectrum of phenotypes associated with genetic variants. However, the phenome or spectrum of all phenotypes associated with genetic variants in extracellular matrix genes is unknown. Here, we analyzed over two million recorded genotype-to-phenotype relationships across hundreds of species to define their extracellular matrix phenomes. By using previously defined matrisomes of humans, mice, zebrafish, Drosophila, and C. elegans, we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (COL1A1, COL2A1) and fibrillin (FBN1) are each associated with more than 150 distinct phenotypes in humans, whereas collagen COL4A1, Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found that MSTN, CTSD, LAMB2, HSPG2, and COL11A2 and their corresponding orthologues have the most phenotypes across species. Out of the 42’558 unique matrisome genotype-to-phenotype relationships across the five species with defined matrisomes, we have constructed interaction networks to identify the underlying molecular components connecting with orthologues phenotypes and with novel phenotypes. Thus, our networks provide a framework to predict unassessed phenotypes and their potential underlying molecular interactions. These frameworks inform on matrisome genotype-to-phenotype relationships and potentially provide a sophisticated choice of biological model system to study human phenotypes and diseases.Highlights7.6% of the human phenome originates from variations in matrisome genes11’671 phenotypes are linked to matrisome genes of humans, mice, zebrafish, Drosophila, and C. elegansExpected top ECM phenotypes are developmental, morphological and structural phenotypesNonobvious top ECM phenotypes include immune system, stress resilience, and age-related phenotypes

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

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