title: Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease.
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.
authors.affiliation: Department of Surgery.|Centre for Genomic Sciences.|Dr Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong SAR, China.
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.affiliation: Department of Surgery.|Centre for Genomic Sciences.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Gui
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Research Institute for Basic Science, Sogang University, Seoul 121-742, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Luzón-Toro
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.affiliation: Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Burzynski
authors.affiliation: UOC Genetica Medica, Istituto Giannina Gaslini, 16148 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lantieri
authors.affiliation: Department of Surgery.
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Berrios
authors.affiliation: Research Institute for Basic Science, Sogang University, Seoul 121-742, Republic of Korea.|Department of Life Science, Sogang University, Seoul 121-742, Republic of Korea.
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Thuy-Linh
authors.initials: TL
authors.lastname: Le
authors.affiliation: Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joke B G M
authors.initials: JB
authors.lastname: Verheij
authors.affiliation: UOC Genetica Medica, Istituto Giannina Gaslini, 16148 Genova, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Matera
authors.affiliation: Centre for Genomic Sciences.|Department of Psychiatry.|State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Nandakumar
authors.affiliation: Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul 121-742, Republic of Korea.
authors.forename: Hyun Sub
authors.initials: HS
authors.lastname: Cheong
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Jeong-Meen
authors.initials: JM
authors.lastname: Seo
authors.affiliation: Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Dae-Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Pediatric Surgery, Severance Children's Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Jung-Tak
authors.initials: JT
authors.lastname: Oh
authors.affiliation: Laboratory of Embryology and Genetics of Congenital Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Institut Imagine, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.affiliation: UOC Genetica Medica, Istituto Giannina Gaslini, 16148 Genova, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
authors.affiliation: Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands.|Stem Cells and Regenerative Medicine, Birth Defects Research Centre UCL Institute of Child Health, London, UK.
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Pediatric Surgery, Seoul National University Children's Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Centre for Genomic Sciences.|Department of Psychiatry.|State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Surgery.|Dr Li Dak-Sum Research Centre, The University of Hong Kong - Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong SAR, China.
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.affiliation: Department of Surgery.|Centre for Genomic Sciences.
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D040121:Semaphorin-3A / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human