Multiple, independent, common variants overlapping known and putative gut enhancers at RET , SEMA3 and NRG1 underlie Hirschsprung disease risk in European ancestry subjects
Multiple, independent, common variants overlapping known and putative gut enhancers at RET , SEMA3 and NRG1 underlie Hirschsprung disease risk in European ancestry subjects
Abstract PurposeHirschsprung disease (HSCR) is a developmental disorder of the enteric nervous system (ENS) characterized by congenital aganglionosis, and where individual cases harbor coding risk variants in ENS genes. Low-penetrance, common, noncoding variants at RET, SEMA3 and NRG1 loci have been associated in HSCR as well, implicating variable gene expression mediated by cis-regulatory element (CRE) variants as the causal mechanism. However, the extent and combinatorial effects of all putative CRE variants within and across these loci on HSCR is unknown. MethodsUsing 583 HSCR subjects, one of the largest samples of European ancestry studied, and genotyping 56 tag variants we evaluated association of all common variants overlapping putative gut CREs and fine-mapped variants at RET, SEMA3 and NRG1. ResultsWe demonstrate that 28 and 8 tag variants, several of which are independent, overlapping putative-enhancers at the RET and SEMA3 loci, respectively, and, 2 fine-mapped tag variants at NRG1 locus, are associated with HSCR. We demonstrate that risk increases with increasing risk allele dosage from multiple variants within and across these loci and varies >25- fold. ConclusionGene regulatory networks in HSCR-relevant cell types quantify the total burden of risk alleles through sensing reduced gene expression of multiple genes on disease.
The Hirschsprung Disease Research Collaborative (HDRC)、Auer Dallas R.、Ross Holly、Nandakumar Priyanka、Kapoor Ashish、Yan Jia、Berrios Courtney、Bollinger Juli、Chakravarti Aravinda、Sosa Maria X.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine||Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at HoustonMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine||Center for Human Genetics and Genomics, New York University School of MedicineMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
基础医学医学研究方法遗传学
Hirschsprung diseaseenhancerpolymorphismgenetic risk
The Hirschsprung Disease Research Collaborative (HDRC),Auer Dallas R.,Ross Holly,Nandakumar Priyanka,Kapoor Ashish,Yan Jia,Berrios Courtney,Bollinger Juli,Chakravarti Aravinda,Sosa Maria X..Multiple, independent, common variants overlapping known and putative gut enhancers at RET , SEMA3 and NRG1 underlie Hirschsprung disease risk in European ancestry subjects[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2020.06.07.138719.点此复制
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