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Title: Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease.
Authors: Tang, Clara Sze-Man
Gui, Hongsheng
Kapoor, Ashish
Kim, Jeong-Hyun
Luzón-Toro, Berta
Pelet, Anna
Burzynski, Grzegorz
Lantieri, Francesca
So, Man-Ting
Berrios, Courtney
Shin, Hyoung Doo
Fernández, Raquel M
Le, Thuy-Linh
Verheij, Joke B G M
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, Hyun-Young
Sham, Pak Chung
Tam, Paul K H
Garcia-Barceló, Maria-Mercè
metadata.dc.subject.mesh: Alleles
Asian People
Genetic Predisposition to Disease
Genome-Wide Association Study
Hirschsprung Disease
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins c-ret
White People
Issue Date: 2016
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.
metadata.dc.identifier.doi: 10.1093/hmg/ddw333
Appears in Collections:Producción 2020

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