A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals

Yoichi Kakuta, Yosuke Kawai, Takeo Naito, Atsushi Hirano, Junji Umeno, Yuta Fuyuno, Zhenqiu Liu, Dalin Li, Takeru Nakano, Yasuhiro Izumiyama, Ryo Ichikawa, Daisuke Okamoto, Hiroshi Nagai, Shin Matsumoto, Katsutoshi Yamamoto, Naonobu Yokoyama, Hirofumi Chiba, Yusuke Shimoyama, Motoyuki Onodera, Rintaro MoroiMasatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Kenichi Negoro, Jun Yasuda, Motohiro Esaki, Katsushi Tokunaga, Minoru Nakamura, Takayuki Matsumoto, Dermot P.B. McGovern, Masao Nagasaki, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)648-658
Number of pages11
JournalJournal of Crohn's and Colitis
Volume13
Issue number5
DOIs
StatePublished - Jan 1 2019

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Genome-Wide Association Study
Crohn Disease
Genes
Single Nucleotide Polymorphism
Odds Ratio
Population
Gene Expression Profiling
Meta-Analysis
Mucous Membrane
Genotype
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Kakuta, Yoichi ; Kawai, Yosuke ; Naito, Takeo ; Hirano, Atsushi ; Umeno, Junji ; Fuyuno, Yuta ; Liu, Zhenqiu ; Li, Dalin ; Nakano, Takeru ; Izumiyama, Yasuhiro ; Ichikawa, Ryo ; Okamoto, Daisuke ; Nagai, Hiroshi ; Matsumoto, Shin ; Yamamoto, Katsutoshi ; Yokoyama, Naonobu ; Chiba, Hirofumi ; Shimoyama, Yusuke ; Onodera, Motoyuki ; Moroi, Rintaro ; Kuroha, Masatake ; Kanazawa, Yoshitake ; Kimura, Tomoya ; Shiga, Hisashi ; Endo, Katsuya ; Negoro, Kenichi ; Yasuda, Jun ; Esaki, Motohiro ; Tokunaga, Katsushi ; Nakamura, Minoru ; Matsumoto, Takayuki ; McGovern, Dermot P.B. ; Nagasaki, Masao ; Kinouchi, Yoshitaka ; Shimosegawa, Tooru ; Masamune, Atsushi. / A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals. In: Journal of Crohn's and Colitis. 2019 ; Vol. 13, No. 5. pp. 648-658.
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abstract = "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.",
author = "Yoichi Kakuta and Yosuke Kawai and Takeo Naito and Atsushi Hirano and Junji Umeno and Yuta Fuyuno and Zhenqiu Liu and Dalin Li and Takeru Nakano and Yasuhiro Izumiyama and Ryo Ichikawa and Daisuke Okamoto and Hiroshi Nagai and Shin Matsumoto and Katsutoshi Yamamoto and Naonobu Yokoyama and Hirofumi Chiba and Yusuke Shimoyama and Motoyuki Onodera and Rintaro Moroi and Masatake Kuroha and Yoshitake Kanazawa and Tomoya Kimura and Hisashi Shiga and Katsuya Endo and Kenichi Negoro and Jun Yasuda and Motohiro Esaki and Katsushi Tokunaga and Minoru Nakamura and Takayuki Matsumoto and McGovern, {Dermot P.B.} and Masao Nagasaki and Yoshitaka Kinouchi and Tooru Shimosegawa and Atsushi Masamune",
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Kakuta, Y, Kawai, Y, Naito, T, Hirano, A, Umeno, J, Fuyuno, Y, Liu, Z, Li, D, Nakano, T, Izumiyama, Y, Ichikawa, R, Okamoto, D, Nagai, H, Matsumoto, S, Yamamoto, K, Yokoyama, N, Chiba, H, Shimoyama, Y, Onodera, M, Moroi, R, Kuroha, M, Kanazawa, Y, Kimura, T, Shiga, H, Endo, K, Negoro, K, Yasuda, J, Esaki, M, Tokunaga, K, Nakamura, M, Matsumoto, T, McGovern, DPB, Nagasaki, M, Kinouchi, Y, Shimosegawa, T & Masamune, A 2019, 'A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals', Journal of Crohn's and Colitis, vol. 13, no. 5, pp. 648-658. https://doi.org/10.1093/ecco-jcc/jjy197

A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals. / Kakuta, Yoichi; Kawai, Yosuke; Naito, Takeo; Hirano, Atsushi; Umeno, Junji; Fuyuno, Yuta; Liu, Zhenqiu; Li, Dalin; Nakano, Takeru; Izumiyama, Yasuhiro; Ichikawa, Ryo; Okamoto, Daisuke; Nagai, Hiroshi; Matsumoto, Shin; Yamamoto, Katsutoshi; Yokoyama, Naonobu; Chiba, Hirofumi; Shimoyama, Yusuke; Onodera, Motoyuki; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Negoro, Kenichi; Yasuda, Jun; Esaki, Motohiro; Tokunaga, Katsushi; Nakamura, Minoru; Matsumoto, Takayuki; McGovern, Dermot P.B.; Nagasaki, Masao; Kinouchi, Yoshitaka; Shimosegawa, Tooru; Masamune, Atsushi.

In: Journal of Crohn's and Colitis, Vol. 13, No. 5, 01.01.2019, p. 648-658.

Research output: Contribution to journalArticle

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

PY - 2019/1/1

Y1 - 2019/1/1

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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