Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms

Kapoor, Ashish; Jiang, Qian; Chatterjee, Satadal; Chakraborty, Prakash; Sosa, Maria X.; Berrios, Courtney; Chakravarti, Aravinda

doi:10.1093/hmg/ddv051

Cited by 64 publications

(97 citation statements)

References 18 publications

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“…A major remaining question is how widespread human susceptibility from common enhancer variants, a defining feature of all complex diseases, is converted to clinical disease (Kapoor et al, 2015). The hypotheses include stochastic effects on gene expression, additional variants in other genes dysregulating other GRNs, and environmental effects on gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, the most frequent coding mutations occur in RET , encoding a receptor tyrosine kinase (Emison et al, 2010; Emison et al, 2005). Surprisingly, significantly greater risk to the more common, isolated, non-syndromic HSCR arises from three polymorphic, low-penetrance non-coding variants at RET (rs2435357, rs2506030) and SEMA3C/D (rs11766001), in patients of European ancestry (Kapoor et al, 2015). Of these, we have shown that the RET intronic variant rs2435357 has high (~24%) allele frequency, disrupts SOX10 binding to a fetal gut enhancer (CRE: RET+3), reduces RET expression and increases Hirschsprung disease (HSCR) risk 4-fold (Emison et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

Chatterjee

Kapoor

Akiyama

et al. 2016

Cell

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116

168

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SUMMARY Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidence that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

Chatterjee

Kapoor

Akiyama

et al. 2016

Cell

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116

168

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“…[18][19][20] The reason for the incomplete migration and development of ganglion cells is as yet not fully understood. Early estimates were that genetic variations could be identified in at least 12% of HSCR cases, which is higher than the expected in the normal population.…”

Section: Genetic Associations Of Hscrmentioning

confidence: 99%

“…The RET intronic SNP rs2435357 has been shown to demonstrate significant frequency differences by affecting RET transcription regulation affecting sex, segment length of aganglionosis, and family recurrence. 18 Mutations affecting the coding of RET mRNA are less common overall and appear more frequently in cases of extended aganglionosis (eg, TCA).…”

Section: Genetic Associations Of Hscrmentioning

confidence: 99%

Hirschsprung disease: current perspectives

Moore¹

2016

OAS

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Hirschsprung disease is a complex congenital condition of the intestine, which is recognized as being of genetic origin and results from a disturbance of the normal development of the enteric nervous system. As a result, aganglionosis of the distal bowel occurs. It is the most common cause of a low intestinal obstruction in the neonate as well as older children. Occurring as an isolated condition in 70% of cases, it may be associated with other associated congenital abnormalities as well as a number of syndromic phenotypes. A number of distinct genetic sites have been identified in these syndromic phenotypes, which identify potential underlying genetic associations of the disease and indicate the probable gene-gene interaction in its pathogenesis. This review looks at the prevalence, congenital associations, and possible genetic factors influencing the development of Hirschsprung disease. Diagnostic dilemmas, surgical management, potential postsurgical complications, and outcomes are also explored.

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“…The 3 common polymorphisms were identified in genome-wide association study of HSCR patients of European ancestry and replicated independently [35, 36] The prevalence of each of the variables listed was compared between patients with and without proximal IND-SH using Welch Two Sample T-test, Fisher’s Exact test, or Permutation Chi-Squared test.…”

Section: Methodsmentioning

confidence: 99%

Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections

Swaminathan¹,

Oron²,

Chatterjee

et al. 2015

Pediatr Dev Pathol

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Intestinal neuronal dysplasia type B (IND) denotes an increased proportion of hyperplastic submucosal ganglia, as resolved histochemically in 15 µm-thick frozen sections. IND has been reported proximal to the aganglionic segment in patients with Hirschsprung disease (HSCR) and is putatively associated with a higher rate of post-surgical dysmotility. We have developed and validated histological criteria to diagnose IND-like submucosal ganglion cell hyperplasia (IND-SH) in paraffin sections, and used the approach to study the incidence and clinical/genetic associations of IND-SH at the proximal margins of HSCR pull-through resection specimens. Full-circumference paraffin sections from the proximal margins of 64 HSCR colonic pull-through specimens and 24 autopsy controls were immunostained for the neuron-specific Hu antigen and nucleated ganglion cells in each submucosal ganglion were counted. In controls, an age-related decline in the relative abundance of “giant” ganglia (≥7 nucleated Hu+ ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean + 3 times the standard deviation) was derived from 15 controls less than 25 weeks of age. No control exceeded this threshold, whereas in the same age range, IND-SH was observed at the proximal margins in 15% (7/46) of HSCR resections, up to 15 cm proximal to the aganglionic segment. No significant correlation was observed between IND-SH and length of or distance from the aganglionic segment, gender, trisomy 21, RET or SEMA3C/D polymorphisms, or clinical outcome, but analysis of more patients with better long-term follow-up will be required to clarify the significance of this histological phenotype.

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Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms

Cited by 64 publications

References 18 publications

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

Hirschsprung disease: current perspectives

Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections

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