Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis

Kazuyoshi Ishigaki, Yuta Kochi, Akari Suzuki, Yumi Tsuchida, Haruka Tsuchiya, Shuji Sumitomo, Kensuke Yamaguchi, Yasuo Nagafuchi, Shinichiro Nakachi, Rika Kato, Keiichi Sakurai, Hirofumi Shoda, Katsunori Ikari, Atsuo Taniguchi, Hisashi Yamanaka, Fuyuki Miya, Tatsuhiko Tsunoda, Yukinori Okada, Yukihide Momozawa, Yoichiro KamataniRyo Yamada, Michiaki Kubo, Keishi Fujio, Kazuhiko Yamamoto

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4 + T cells, CD8 + T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4 + T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.

Original languageEnglish
Pages (from-to)1120-1125
Number of pages6
JournalNature Genetics
Volume49
Issue number7
DOIs
Publication statusPublished - 01-07-2017

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Quantitative Trait Loci
Rheumatoid Arthritis
T-Lymphocytes
Immune Complex Diseases
Genes
Gene Expression
Epigenomics
Natural Killer Cells
Monocytes
Healthy Volunteers
B-Lymphocytes
Up-Regulation
Tumor Necrosis Factor-alpha
Alleles
Databases
Cytokines

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Ishigaki, K., Kochi, Y., Suzuki, A., Tsuchida, Y., Tsuchiya, H., Sumitomo, S., ... Yamamoto, K. (2017). Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nature Genetics, 49(7), 1120-1125. https://doi.org/10.1038/ng.3885
Ishigaki, Kazuyoshi ; Kochi, Yuta ; Suzuki, Akari ; Tsuchida, Yumi ; Tsuchiya, Haruka ; Sumitomo, Shuji ; Yamaguchi, Kensuke ; Nagafuchi, Yasuo ; Nakachi, Shinichiro ; Kato, Rika ; Sakurai, Keiichi ; Shoda, Hirofumi ; Ikari, Katsunori ; Taniguchi, Atsuo ; Yamanaka, Hisashi ; Miya, Fuyuki ; Tsunoda, Tatsuhiko ; Okada, Yukinori ; Momozawa, Yukihide ; Kamatani, Yoichiro ; Yamada, Ryo ; Kubo, Michiaki ; Fujio, Keishi ; Yamamoto, Kazuhiko. / Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. In: Nature Genetics. 2017 ; Vol. 49, No. 7. pp. 1120-1125.
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abstract = "Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4 + T cells, CD8 + T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4 + T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.",
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Ishigaki, K, Kochi, Y, Suzuki, A, Tsuchida, Y, Tsuchiya, H, Sumitomo, S, Yamaguchi, K, Nagafuchi, Y, Nakachi, S, Kato, R, Sakurai, K, Shoda, H, Ikari, K, Taniguchi, A, Yamanaka, H, Miya, F, Tsunoda, T, Okada, Y, Momozawa, Y, Kamatani, Y, Yamada, R, Kubo, M, Fujio, K & Yamamoto, K 2017, 'Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis', Nature Genetics, vol. 49, no. 7, pp. 1120-1125. https://doi.org/10.1038/ng.3885

Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. / Ishigaki, Kazuyoshi; Kochi, Yuta; Suzuki, Akari; Tsuchida, Yumi; Tsuchiya, Haruka; Sumitomo, Shuji; Yamaguchi, Kensuke; Nagafuchi, Yasuo; Nakachi, Shinichiro; Kato, Rika; Sakurai, Keiichi; Shoda, Hirofumi; Ikari, Katsunori; Taniguchi, Atsuo; Yamanaka, Hisashi; Miya, Fuyuki; Tsunoda, Tatsuhiko; Okada, Yukinori; Momozawa, Yukihide; Kamatani, Yoichiro; Yamada, Ryo; Kubo, Michiaki; Fujio, Keishi; Yamamoto, Kazuhiko.

In: Nature Genetics, Vol. 49, No. 7, 01.07.2017, p. 1120-1125.

Research output: Contribution to journalArticle

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AU - Ishigaki, Kazuyoshi

AU - Kochi, Yuta

AU - Suzuki, Akari

AU - Tsuchida, Yumi

AU - Tsuchiya, Haruka

AU - Sumitomo, Shuji

AU - Yamaguchi, Kensuke

AU - Nagafuchi, Yasuo

AU - Nakachi, Shinichiro

AU - Kato, Rika

AU - Sakurai, Keiichi

AU - Shoda, Hirofumi

AU - Ikari, Katsunori

AU - Taniguchi, Atsuo

AU - Yamanaka, Hisashi

AU - Miya, Fuyuki

AU - Tsunoda, Tatsuhiko

AU - Okada, Yukinori

AU - Momozawa, Yukihide

AU - Kamatani, Yoichiro

AU - Yamada, Ryo

AU - Kubo, Michiaki

AU - Fujio, Keishi

AU - Yamamoto, Kazuhiko

PY - 2017/7/1

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Ishigaki K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S et al. Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nature Genetics. 2017 Jul 1;49(7):1120-1125. https://doi.org/10.1038/ng.3885