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A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease

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A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease Jeong-Hyun Kim1,2, Hyun Sub Cheong3, Jae Hoon Sul4, Jeong-Meen Seo5, Dae-Yeon Kim6, Jung-Tak Oh7, Kwi-Won Park8, Hyun-Young Kim8, Soo-Min Jung5, Kyuwhan Jung9, Min Jeng Cho10, Joon Seol Bae11, Hyoung Doo Shin1,2,3* 1 Research Institute for Basic Science, Sogang University, Seoul, Republic of Korea, 2 Department of Life Science, Sogang University, Seoul, Republic of Korea, 3 Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of Korea, 4 Department of Computer Science, University of California Los Angeles, Los Angeles, California, United States of America, 5 Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 6 Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 7 Department of Pediatric Surgery, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, 8 Department of Pediatric Surgery, Seoul National University Children’s Hospital, Seoul, Republic of Korea, 9 Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea, 10 Department of Surgery, Konkuk University Medical Center, Seoul, Republic of Korea, 11 Laboratory of Translational Genomics, Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea Abstract Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Although RET is a well-established risk factor, a recent genome-wide association study (GWAS) of HSCR has identified NRG1 as an additional susceptibility locus. To discover additional risk loci, we performed a GWAS of 123 sporadic HSCR patients and 432 unaffected controls using a large-scale platform with coverage of over 1 million polymorphic markers. The result was that our study replicated the findings of RET-CSGALNACT2- 219 213 RASGEF1A genomic region (rawP = 5.69610 before a Bonferroni correction; corrP = 4.31610 after a Bonferroni 26 correction) and NRG1 as susceptibility loci. In addition, this study identified SLC6A20 (adjP =2.71610 ), RORA 25 25 (adjP = 1.26610 ), and ABCC9 (adjP = 1.86610 ) as new potential susceptibility loci under adjusting the already known loci on the RET-CSGALNACT2-RASGEF1A and NRG1 regions, although none of the SNPs in these genes passed the Bonferroni correction. In further subgroup analysis, the RET-CSGALNACT2-RASGEF1A genomic region was observed to have different 25 24 significance levels among subgroups: short-segment (S-HSCR, corrP = 1.71610 ), long-segment (L-HSCR, corrP = 6.66610 ), and total colonic aganglionosis (TCA, corrP.0.05). This differential pattern in the significance level suggests that other genomic loci or mechanisms may affect the length of aganglionosis in HSCR subgroups during enteric nervous system (ENS) development. Although functional evaluations are needed, our findings might facilitate improved understanding of the mechanisms of HSCR pathogenesis. Citation: Kim J-H, Cheong HS, Sul JH, Seo J-M, Kim D-Y, et al. (2014) A Genome-Wide Association Study Identifies Potential Susceptibility Loci for Hirschsprung Disease. PLoS ONE 9(10): e110292. doi:10.1371/journal.pone.0110292 Editor: Stacey Cherny, University of Hong Kong, Hong Kong Received May 26, 2014; Accepted September 11, 2014; Published October 13, 2014 Copyright: ß 2014 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0007857 and 2012-0006690) and the Ministry of Education (2013R1A1A2008335). The funders had norolein study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors of this manuscript have read the journal’s policy and have the following competing interests: SNP Genetics, Inc. provided the iScan scanner instrument and GenomeStudio software used in the research. Authors employed in the company also were involved in the study design, data collection and analysis, decision to publish and preparation of the manuscript. Jeong-Meen Seo is employed by Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Republic of Korea and Joon Seol Bae is employed by Laboratory of Translational Genomics, Samsung Genome Institute, Samsung Medical Center, Seoul 135-710, Republic of Korea. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. * Email: [email protected] Introduction beyond the upper sigmoid, (2) long-segment (L-HSCR, ,15%) with aganglionosis affecting longer tracts of the colon, and (3) total Hirschsprung disease (HSCR, or aganglionic megacolon) is a colonic aganglionosis (TCA, ,5%) [1,2]. Genetic variations in rare congenital disease (1 in 5000 live births) that leads to intestinal eight genes, including RET, have been implicated in less than 30% obstruction or chronic constipation. HSCR manifests a sex- of HSCR development, indicating the need to identify additional dependent penetrance (male:female ratio of ,4:1) and involves HSCR-causing variations. mostly sporadic cases; however, 5–20% are familial forms. Based The RET proto-oncogene, encoding a tyrosine-kinase receptor, on the length of aganglionosis, patients can be further classified has been identified as the major HSCR gene. In particular, a into three groups as follows: (1) short-segment (S-HSCR, ,80% of common variant rs2435357 (also known as RET+3) within a cases) with aganglionosis affecting the rectum and not extending conserved enhancer-like sequence in intron 1 of RET showed a PLOS ONE | www.plosone.org 1 October 2014 | Volume 9 | Issue 10 | e110292 GWAS of Hirschsprung Disease significant association with HSCR susceptibility, with different DNAs on Illumina’s HumanOmni1-Quad BeadChip (Illumina, genetic effects between male and female patients [3]. Since this San Diego, USA), according to the manufacturer’s protocol. All variant is located in an enhancer-like sequence, it was further samples were scanned using the Illumina iScan system (Illumina), speculated that additional factors might interact with this variant and the normalized bead intensity data were loaded into the to affect RET expression. Two downstream genes that are near GenomeStudio software (Illumina). Considering a potential RET, CSGALNACT2 and RASGEF1A, are differentially ex- association between rare variants and rare diseases such as pressed between the colon and small intestine [3], although the HSCR, this study included all polymorphic markers for association functions of these genes have not been adequately characterized. analysis. For 1,140,419 markers on the chip, SNP marker quality Mutations in other genes (EDNRB, GDNF, NRTN, SOX10, control (QC) was applied as follows: (1) only SNP with call rate (. etc.) have also been identified as contributing to HSCR 98%, 995,666 markers) in both cases and controls was included, (2) development [1,2,4,5]. Recently, the first genome-wide association 221,556 monomorphic markers were excluded, and (3) visual study (GWAS) of HSCR has additionally identified neuregulin 1 inspection of the genotype cluster image was performed for the (NRG1), one of the molecular regulators in the development and SNPs with deviation from Hardy-Weinberg equilibrium (HWE, maintenance of the enteric nervous system (ENS), as a suscepti- P,0.0001), and 16,850 SNPs deviating from HWE were excluded bility locus for HSCR [6]. Follow-up studies have also evaluated from the analysis. The 757,260 markers that remained after QC the potential effects of NRG1 on HSCR, including aberrant were ultimately used for further association analysis. NRG1 expression [7,8]; however, results from these studies suggest that other alleles or epigenetic factors might affect NRG1 Statistics expression. Moreover, still other factors (for instance, APOB, Associations of genotype distributions were calculated by logistic RELN, GAL, etc.) have been proposed that may be associated regression analysis using HelixTree software (Golden Helix, with HSCR development [9,10]. Bozeman, MT, USA). The possible population stratification was Given that HSCR is a heterogeneous disorder, new confounders examined by PCA using HelixTree software. A Bonferroni with small-to-modest effects on HSCR development have yet to be correction applied by the number of independent SNPs discovered. RET coding sequence mutations account for about (757,260), which resulted in the threshold of GWAS significance 28 50% in familial HSCR and 15–20% in sporadic HSCR [1]. In this (corrP = 6.6610 ), was calculated. In order to remove the effects study, we have performed GWAS using sporadic HSCR to of primary top signals from the known RET-CSGALNACT2- discover additional risk loci and to validate
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