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 Kamatani; Ryo Yamada; Michiaki Kubo; Keishi Fujio; Kazuhiko Yamamoto

doi:10.1038/ng.3885

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

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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.

Original language	English
Pages (from-to)	1120-1125
Number of pages	6
Journal	Nature Genetics
Volume	49
Issue number	7
DOIs	https://doi.org/10.1038/ng.3885
Publication status	Published - 01-07-2017

All Science Journal Classification (ASJC) codes

Genetics

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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., ... 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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title = "Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis",

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.",

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

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doi = "10.1038/ng.3885",

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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 journal › Article › peer-review

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AU - Sumitomo, Shuji

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AU - Sakurai, Keiichi

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AU - Yamanaka, Hisashi

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AU - Kamatani, Yoichiro

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

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