TY - JOUR
T1 - A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals
AU - Kakuta, Yoichi
AU - Kawai, Yosuke
AU - Naito, Takeo
AU - Hirano, Atsushi
AU - Umeno, Junji
AU - Fuyuno, Yuta
AU - Liu, Zhenqiu
AU - Li, Dalin
AU - Nakano, Takeru
AU - Izumiyama, Yasuhiro
AU - Ichikawa, Ryo
AU - Okamoto, Daisuke
AU - Nagai, Hiroshi
AU - Matsumoto, Shin
AU - Yamamoto, Katsutoshi
AU - Yokoyama, Naonobu
AU - Chiba, Hirofumi
AU - Shimoyama, Yusuke
AU - Onodera, Motoyuki
AU - Moroi, Rintaro
AU - Kuroha, Masatake
AU - Kanazawa, Yoshitake
AU - Kimura, Tomoya
AU - Shiga, Hisashi
AU - Endo, Katsuya
AU - Negoro, Kenichi
AU - Yasuda, Jun
AU - Esaki, Motohiro
AU - Tokunaga, Katsushi
AU - Nakamura, Minoru
AU - Matsumoto, Takayuki
AU - McGovern, Dermot P.B.
AU - Nagasaki, Masao
AU - Kinouchi, Yoshitaka
AU - Shimosegawa, Tooru
AU - Masamune, Atsushi
N1 - Funding Information:
SNP genotyping was supported in part by the Centre of Innovation Program from the Japan Science and Technology Agency, JST. Computational resources were provided in part by the ToMMo supercomputer system. We would like to thank the member of MENDEL study group for sharing the genetic data. Author Contributions Y. Kakuta, Y. Kawai, MN, and Y. Kinouchi designed the study. T. Naito, Y. Kawai, AH, JU, YF, DO, HC, JY, and Y. Kakuta acquired data. AH, JU, YF, T. Nakano, YI, RI, DO, HN, SM, KY, NY, HC, YS, MO, RM, MK, HS, Y. Kanazawa, TK, KE, and ME recruited patients. Y. Kakuta, Y. Kawai, ZL, DL, DMcG, and MN analysed data. Y. Kakuta, Y. Kinouchi, AM, TS, and DMcGn drafted the manuscript. MN, MEi, KT, and TM provided samples.
Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers JP15H04805, by AMED under Grant Number JP18kk0305002, and in part by the Tohoku Medical Megabank Project [Special Account for reconstruction from the Great East Japan Earthquake].
Funding Information:
MN reports grants from Obtain, the research grant from Toshiba Corporation during the study period, outside the submitted work; AH reports grants from AbbVie GK, outside the submitted work; TMreports grants from Mitsubishi Tanabe Pharma Corporation, EA pharma Co., Nippon Kayaku Co., Janssen Pharmaceutical K.K., AbbVie GK, and Kyorin Pharmaceutical Co., outside the submitted work. The other authors have no conflicts of interest to declare.
Funding Information:
aDivision of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan bTohoku Medical Megabank Organisation, Tohoku University, Sendai, Japan cDepartment of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan dF. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Centre, Los Angeles, CA, USA eDepartment of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan fClinical Research Centre, National Hospital Organisation [NHO] Nagasaki Medical Centre, Omura, Japan gDivision of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan hHealth Administration Centre, Centre for the Advancement of Higher Education, Tohoku University, Sendai, Japan
Publisher Copyright:
Copyright © 2018 European Crohn's and Colitis Organisation (ECCO).
PY - 2019/4/26
Y1 - 2019/4/26
N2 - Background and Aims: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10-19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10-6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10-8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions: RAP1A is a novel susceptibility locus for CD in the Japanese population.
AB - Background and Aims: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10-19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10-6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10-8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions: RAP1A is a novel susceptibility locus for CD in the Japanese population.
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U2 - 10.1093/ecco-jcc/jjy197
DO - 10.1093/ecco-jcc/jjy197
M3 - Article
C2 - 30500874
AN - SCOPUS:85068490457
SN - 1873-9946
VL - 13
SP - 648
EP - 658
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 5
ER -