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Hum Mol Genet. 2016 Dec 1;25(23):5265-5275. doi: 10.1093/hmg/ddw333.

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

Author information

1
Department of Surgery.
2
Centre for Genomic Sciences.
3
Dr Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong SAR, China.
4
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Research Institute for Basic Science, Sogang University, Seoul 121-742, Republic of Korea.
6
Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
7
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
8
Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France.
9
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
10
Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands.
11
UOC Genetica Medica, Istituto Giannina Gaslini, 16148 Genova, Italy.
12
Department of Life Science, Sogang University, Seoul 121-742, Republic of Korea.
13
Department of Psychiatry.
14
State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
15
Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul 121-742, Republic of Korea.
16
Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
17
Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
18
Department of Pediatric Surgery, Severance Children's Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
19
Stem Cells and Regenerative Medicine, Birth Defects Research Centre UCL Institute of Child Health, London, UK.
20
Department of Pediatric Surgery, Seoul National University Children's Hospital, Seoul 110-744, Republic of Korea.

Abstract

Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs.

PMID:
27702942
PMCID:
PMC6078638
DOI:
10.1093/hmg/ddw333
[Indexed for MEDLINE]
Free PMC Article

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