Format

Send to

Choose Destination
Gastroenterology. 2018 Dec;155(6):1908-1922.e5. doi: 10.1053/j.gastro.2018.09.012. Epub 2018 Sep 12.

Identification of Genes Associated With Hirschsprung Disease, Based on Whole-Genome Sequence Analysis, and Potential Effects on Enteric Nervous System Development.

Author information

1
Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China; Dr Li Dak-Sum Research Centre, The University of Hong Kong, Pokfulam, Hong Kong, China.
2
Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
3
Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, China.
4
Hebei Medical University Second Hospital, Shijiazhuang, Hebei, China.
5
National Hospital of Pediatrics, Ha Noi, Viet Nam.
6
Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
7
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
8
Department of Paediatric Surgery, Shandong Medical University, Shandong, China.
9
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
10
The Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong, China.
11
Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China.
12
Changchun Children's Hospital, Changchun, Jilin, China.
13
Bayi Children's Hospital, General Hospital of Beijing Military Region, Beijing, China.
14
Shenzhen Children's Hospital, Shenzhen, Guangdong, China.
15
Zhejiang Children's Hospital, Hangzhou, Zhejiang, China.
16
School of Biological Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
17
Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
18
Department of Paediatric Surgery, Shengjing Hospital, China Medical University, Shenyang, China.
19
Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China; Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
20
Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address: mmgarcia@hku.hk.
21
Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address: engan@hku.hk.

Abstract

BACKGROUND & AIMS:

Hirschsprung disease, or congenital aganglionosis, is believed to be oligogenic-that is, caused by multiple genetic factors. We performed whole-genome sequence analyses of patients with Hirschsprung disease to identify genetic factors that contribute to disease development and analyzed the functional effects of these variants.

METHODS:

We performed whole-genome sequence analyses of 443 patients with short-segment disease, recruited from hospitals in China and Vietnam, and 493 ethnically matched individuals without Hirschsprung disease (controls). We performed genome-wide association analyses and gene-based rare-variant burden tests to identify rare and common disease-associated variants and study their interactions. We obtained induced pluripotent stem cell (iPSC) lines from 4 patients with Hirschsprung disease and 2 control individuals, and we used these to generate enteric neural crest cells for transcriptomic analyses. We assessed the neuronal lineage differentiation capability of iPSC-derived enteric neural crest cells using an in vitro differentiation assay.

RESULTS:

We identified 4 susceptibility loci, including 1 in the phospholipase D1 gene (PLD1) (P = 7.4 × 10-7). The patients had a significant excess of rare protein-altering variants in genes previously associated with Hirschsprung disease and in the β-secretase 2 gene (BACE2) (P = 2.9 × 10-6). The epistatic effects of common and rare variants across these loci provided a sensitized background that increased risk for the disease. In studies of the iPSCs, we observed common and distinct pathways associated with variants in RET that affect risk. In functional assays, we found variants in BACE2 to protect enteric neurons from apoptosis. We propose that alterations in BACE1 signaling via amyloid β precursor protein and BACE2 contribute to pathogenesis of Hirschsprung disease.

CONCLUSIONS:

In whole-genome sequence analyses of patients with Hirschsprung disease, we identified rare and common variants associated with disease risk. Using iPSC cells, we discovered some functional effects of these variants.

KEYWORDS:

Amyloid Beta; CRISPR/Cas9; Enteric Nervous System; Genetics

PMID:
30217742
DOI:
10.1053/j.gastro.2018.09.012
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center