Genome-wide association study of inflammatory bowel disease using population optimized array and reference panel in Japanese

• Project/Area Number: 15H04805
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tohoku University
• Principal Investigator: Kakuta Yoichi 東北大学, 大学病院, 助教 (50509205)
• Co-Investigator(Kenkyū-buntansha): 木内 喜孝 東北大学, 高度教養教育・学生支援機構, 教授 (20250780) ; 黒羽 正剛 東北大学, 大学病院, 助教 (70709469)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 炎症性腸疾患 / クローン病 / 疾患感受性遺伝子 / 潰瘍性大腸炎 / 遺伝学 / 消化器内科学 / 感受性遺伝子

Outline of Final Research Achievements

Several GWASs revealed more than 200 susceptibility loci for IBD. We built a 1KJPN panel containing genomic variations obtained by whole-genome resequencing of 1070 Japanese individuals,and developed the Japonica Array optimized for genotyping and imputing the Japanese population. To clarify the Japanese-specific genetic background of Crohn’s disease (CD), we performed GWAS using a population-optimized SNP array and imputation.
Genotyping data of 7,934,670 SNPs from 737 Japanese CD patients and 2188 controls were analyzed. SNPs located in three known loci, TNFSF15, MHC, and ZNF365, 4p14 showed significant associations with CD. Locus rs488200, located on an intron of RAP1A, was the top hit of novel candidate loci (p=8.85E-8, OR=1.43). A previous report indicated that the underexpression of the RAP1A gene increases the risk of CD because Rap1 regulates T-cell circulation, thereby preventing the onset of colitis in a mouse model. RAP1A is a novel candidate susceptibility gene for CD.

Research Products

• [Int'l Joint Research] ワシントン大学/シーダーズサイナイ医療センター(米国)
• [Journal Article] Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease (2018)
  • Author(s): Chiba Hirofumi、Kakuta Yoichi、Kinouchi Yoshitaka、Kawai Yosuke、Watanabe Kazuhiro、Nagao Munenori、Naito Takeo、Onodera Motoyuki、Moroi Rintaro、Kuroha Masatake、Kanazawa Yoshitake、Kimura Tomoya、Shiga Hisashi、Endo Katsuya、Negoro Kenichi、Nagasaki Masao、Unno Michiaki、Shimosegawa Tooru
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0194036-e0194036
  • DOI: 10.1371/journal.pone.0194036
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and genetic risk factors for decreased bone mineral density in Japanese patients with inflammatory bowel disease (2018)
  • Author(s): Naito T, Yokoyama N, Kakuta Y, Ueno K, Kawai Y, Onodera M, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Endo K, Nagasaki M, Masamune A, Kinouchi Y, Shimosegawa T
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 11 Pages: 1873-1881
  • DOI: 10.1111/jgh.14149
  • Peer Reviewed
• [Journal Article] Increased expression of IL12B mRNA transcribed from the risk haplotype for Crohn’s disease is a risk factor for disease relapse in Japanese patients (2017)
  • Author(s): Kakuta Yoichi、Kimura Tomoya、Negoro Kenichi、Kuroha Masatake、Shiga Hisashi、Endo Katsuya、Kinouchi Yoshitaka、Shimosegawa Tooru
  • Journal Title: J Gastroenterol Volume: 52 Issue: 12 Pages: 1230-1239
  • DOI: 10.1007/s00535-017-1322-5
  • Peer Reviewed
• [Journal Article] LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients (2017)
  • Author(s): Liu TC, Naito T, Liu Z, VanDussen KL, Haritunians T, Li D, Endo K, Kawai Y, Nagasaki M, Kinouchi Y, McGovern DP, Shimosegawa T, Kakuta Y, Stappenbeck TS
  • Journal Title: JCI Insight Volume: 印刷中 Issue: 6
  • DOI: 10.1172/jci.insight.91917
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Population-optimized SNP array reveals RAP1A as a novel candidate susceptibility gene for Crohn’s disease in Japanese individuals (2017)
  • Author(s): Yoichi Kakuta, Yosuke Kawai, Takeo Naito, Atsushi Hirano, Junji Umeno, Keiichiro Hiramoto, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Katsuya Endo, Yoshitaka Kinouchi, Motohiro Esaki, Masao Nagasaki, Tooru Shimosegawa
  • Organizer: Digestive Disease Week 2017
  • Int'l Joint Research
• [Presentation] 個人ゲノム情報から考えるIBD診療の将来像 (2017)
  • Author(s): 角田洋一、木内喜孝、下瀬川徹
  • Organizer: 第8回日本炎症性腸疾患学会学術集会
  • Invited
• [Presentation] Population-optimized SNP array reveals RAP1A as a novel candidate susceptibility gene for Crohn’s disease in Japanese individuals (2017)
  • Author(s): Yoichi Kakuta, Yosuke Kawai, Takeo Naito, Atsushi Hirano, Junji Umeno, Keiichiro Hiramoto, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura1 Katsuya Endo, Yoshitaka Kinouchi, Motohiro Esaki, Masao Nagasaki, Tooru Shimosegawa
  • Organizer: Digestive Disease Week 2017
  • Place of Presentation: Chicago, USA
  • Int'l Joint Research
• [Presentation] Paneth Cell Phenotype is Associated With Novel Genetic Determinants and Clinical Outcome in Japanese Crohn's Disease Patients (2016)
  • Author(s): Takeo Naito, Ta-Chiang Liu, Yoichi Kakuta, Richard Head, Zhenqiu Liu, Talin Haritunians, Dalin Li, Katsuya Endo, Yoshitaka Kinouchi, Dermot McGovern, Thaddeus Stappenbeck, Tooru Shimosegawa
  • Organizer: Digestive Disease Week 2016
  • Place of Presentation: San Diego, USA
  • Int'l Joint Research
• [Presentation] 人種最適化ジェノタイピングアレイによるゲノム解析から見えた日本人炎症性腸疾患の病因・病態にかかわる新たなDisease Pathway (2015)
  • Author(s): ○角田洋一、木内喜孝、内藤健夫、黒羽正剛、木村智哉、遠藤克哉、下瀬川徹
  • Organizer: G-plus2015
  • Place of Presentation: ホテルイースト２１（東京）
  • Year and Date: 2015-12-19