<i>Trans</i>-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease

Tang, Clara S.; Gui, Hongsheng; Kapoor, Ashish; Kim, Jeong Hyun; Lasa, Berta; Pelet, Anna; Burzynski, Grzegorz M.; Lantieri, Francesca; So, Man Ting; Berrios, Courtney; Shin, Hyoung Doo; Fernández, Raquel M.; Le, Thuy Linh; Verheij, Joanne; Matera, Ivana; Cherny, Stacey S.; Nandakumar, Priyanka; Cheong, Hyun Sub; Antiñolo, Guillermo; Amiel, Jeanne; Seo, Jeong Meen; Kim, Dae Yeon; Oh, Jung Tak; Lyonnet, Stanislas; Borrego, Salud; Ceccherini, Isabella; Hofstra, Robert M.W.; Chakravarti, Aravinda; Kim, Ho; Sham, Pak C.; Tam, Paul Kwong‐Hang; García-Barceló, Maria Mercè

doi:10.1093/hmg/ddw333

Cited by 32 publications

(39 citation statements)

References 54 publications

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“…Similarly, our replicated SEMA3 variant is also in LD with rs80227144 hg19.chr7:g.84349842C>A, the previously reported lead SEMA3 SNP [12] (r 2 of rs117617821 −rs80227144 = 0.97) ( Figure S5). In line with previous studies based on Caucasian individuals [9,12], the NRG1 locus only showed suggestive significance in the discovery cohort (lowest P = 9.83 × 10 −6 for rs73250444 hg19.chr8: g.32252694A>C) ( Figure S3a) and did not replicate ( Table 1). The previously reported lead NRG1 SNP in East Asians [12] was even less significantly associated in our data (rs7005606 hg19.chr8:g.32401501T>G; P = 5.22 × 10 −5 ) ( Figure S3b).…”

Section: Gwas Confirms Known Ret and Sema3 Susceptibility Variantssupporting

confidence: 84%

“…Rare high-penetrance mutations have been found in genes associated with the development of the enteric nervous system, but they cumulatively explain <10% of cases [9]. Recent HSCR genome-wide association studies (GWAS) have found significantly greater phenotypic variation in common associated variants at RET, SEMA3, and NRG1 loci, but they still fail to explain all of its heritability [9][10][11][12][13]. Therefore, it is likely that additional common or lowfrequency genetic variants associated with isolated HSCR are yet to be found.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

et al. 2018

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Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

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Section: Gwas Confirms Known Ret and Sema3 Susceptibility Variantssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

et al. 2018

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“…Better than the previous implication of ErbB/Nrg1 signaling in postnatal enteric ganglia in vivo (40) or in vitro (41), it could explain that common variants of Neuregulin-1, the ErbB3 ligand, are associated with Hirschsprung's disease, which results from a partial agenesis of enteric ganglia (42). Given the missing heritability in Hirschprung disease, our results are also a suggestion to look for ErbB3 variants.…”

Section: Discussionmentioning

confidence: 53%

Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest

Espinosa-Medina

Jevans

Boismoreau

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

107

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Most of the enteric nervous system derives from the "vagal" neural crest, lying at the level of somites 1-7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the "vagal crest" subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3-7 belong to the crest streams contributing to sympathetic chains: they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.enteric nervous system | neural crest | chicken | mouse | Neuregulin1

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“…In the past few years, the identification of novel susceptibility genes and variants for HSCR was based on the use of GWAS,GWES 20,25,[38][39][40][154][155][156][157][158][159][160][161] and next-generation sequencing (NGS) approaches. [162][163][164][165][166][167][168][169][170] All of them have fairly improved our knowledge about the genetic background of the disease.…”

Section: New Approachesmentioning

confidence: 99%

What is new about the genetic background of Hirschsprung disease?

et al. 2019

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Hirschsprung disease (HSCR) is a rare congenital disorder caused by an incorrect enteric nervous system development due to a failure in migration, proliferation, differentiation and/or survival of enteric neural crest cells. HSCR is a complex genetic disease, where alterations at different molecular levels are required for the manifestation of the disease. In addition, a wide spectrum of mutations affecting many different genes cause HSCR, although the occurrence and severity of HSCR from many cases still remain unexplained. This review summarizes the current knowledge about molecular genetic basis of HSCR.

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Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease

Cited by 32 publications

References 54 publications

Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus

Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest

What is new about the genetic background of Hirschsprung disease?

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