Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Masahiro Nakatochi; Masahiro Kanai; Akiyoshi Nakayama; Asahi Hishida; Yusuke Kawamura; Sahoko Ichihara; Masato Akiyama; Hiroaki Ikezaki; Norihiro Furusyo; Seiko Shimizu; Ken Yamamoto; Makoto Hirata; Rieko Okada; Sayo Kawai; Makoto Kawaguchi; Yuichiro Nishida; Chisato Shimanoe; Rie Ibusuki; Toshiro Takezaki; Mayuko Nakajima; Mikiya Takao; Etsuko Ozaki; Daisuke Matsui; Takeshi Nishiyama; Sadao Suzuki; Naoyuki Takashima; Yoshikuni Kita; Kaori Endoh; Kiyonori Kuriki; Hirokazu Uemura; Kokichi Arisawa; Isao Oze; Keitaro Matsuo; Yohko Nakamura; Haruo Mikami; Takashi Tamura; Hiroshi Nakashima; Takahiro Nakamura; Norihiro Kato; Koichi Matsuda; Yoshinori Murakami; Tatsuaki Matsubara; Mariko Naito; Michiaki Kubo; Yoichiro Kamatani; Nariyoshi Shinomiya; Mitsuhiro Yokota; Kenji Wakai; Yukinori Okada; Hirotaka Matsuo

doi:10.1038/s42003-019-0339-0

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Masahiro Nakatochi, Masahiro Kanai, Akiyoshi Nakayama, Asahi Hishida, Yusuke Kawamura, Sahoko Ichihara, Masato Akiyama, Hiroaki Ikezaki, Norihiro Furusyo, Seiko Shimizu, Ken Yamamoto, Makoto Hirata, Rieko Okada, Sayo Kawai, Makoto Kawaguchi, Yuichiro Nishida, Chisato Shimanoe, Rie Ibusuki, Toshiro Takezaki, Mayuko NakajimaMikiya Takao, Etsuko Ozaki, Daisuke Matsui, Takeshi Nishiyama, Sadao Suzuki, Naoyuki Takashima, Yoshikuni Kita, Kaori Endoh, Kiyonori Kuriki, Hirokazu Uemura, Kokichi Arisawa, Isao Oze, Keitaro Matsuo, Yohko Nakamura, Haruo Mikami, Takashi Tamura, Hiroshi Nakashima, Takahiro Nakamura, Norihiro Kato, Koichi Matsuda, Yoshinori Murakami, Tatsuaki Matsubara, Mariko Naito, Michiaki Kubo, Yoichiro Kamatani, Nariyoshi Shinomiya, Mitsuhiro Yokota, Kenji Wakai, Yukinori Okada, Hirotaka Matsuo

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10^–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.

Original language	English
Article number	115
Journal	Communications Biology
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s42003-019-0339-0
Publication status	Published - Dec 1 2019

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Medicine (miscellaneous)

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Nakatochi, M., Kanai, M., Nakayama, A., Hishida, A., Kawamura, Y., Ichihara, S., Akiyama, M., Ikezaki, H., Furusyo, N., Shimizu, S., Yamamoto, K., Hirata, M., Okada, R., Kawai, S., Kawaguchi, M., Nishida, Y., Shimanoe, C., Ibusuki, R., Takezaki, T., ... Matsuo, H. (2019). Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. Communications Biology, 2(1), [115]. https://doi.org/10.1038/s42003-019-0339-0

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. / Nakatochi, Masahiro; Kanai, Masahiro; Nakayama, Akiyoshi; Hishida, Asahi; Kawamura, Yusuke; Ichihara, Sahoko; Akiyama, Masato ; Ikezaki, Hiroaki; Furusyo, Norihiro; Shimizu, Seiko; Yamamoto, Ken; Hirata, Makoto; Okada, Rieko; Kawai, Sayo; Kawaguchi, Makoto; Nishida, Yuichiro; Shimanoe, Chisato; Ibusuki, Rie; Takezaki, Toshiro; Nakajima, Mayuko; Takao, Mikiya; Ozaki, Etsuko; Matsui, Daisuke; Nishiyama, Takeshi; Suzuki, Sadao; Takashima, Naoyuki; Kita, Yoshikuni; Endoh, Kaori; Kuriki, Kiyonori; Uemura, Hirokazu; Arisawa, Kokichi; Oze, Isao; Matsuo, Keitaro; Nakamura, Yohko; Mikami, Haruo; Tamura, Takashi; Nakashima, Hiroshi; Nakamura, Takahiro; Kato, Norihiro; Matsuda, Koichi; Murakami, Yoshinori; Matsubara, Tatsuaki; Naito, Mariko; Kubo, Michiaki; Kamatani, Yoichiro; Shinomiya, Nariyoshi; Yokota, Mitsuhiro; Wakai, Kenji; Okada, Yukinori; Matsuo, Hirotaka.

In: Communications Biology, Vol. 2, No. 1, 115, 01.12.2019.

Research output: Contribution to journal › Article › peer-review

Nakatochi, M, Kanai, M, Nakayama, A, Hishida, A, Kawamura, Y, Ichihara, S, Akiyama, M , Ikezaki, H, Furusyo, N, Shimizu, S, Yamamoto, K, Hirata, M, Okada, R, Kawai, S, Kawaguchi, M, Nishida, Y, Shimanoe, C, Ibusuki, R, Takezaki, T, Nakajima, M, Takao, M, Ozaki, E, Matsui, D, Nishiyama, T, Suzuki, S, Takashima, N, Kita, Y, Endoh, K, Kuriki, K, Uemura, H, Arisawa, K, Oze, I, Matsuo, K, Nakamura, Y, Mikami, H, Tamura, T, Nakashima, H, Nakamura, T, Kato, N, Matsuda, K, Murakami, Y, Matsubara, T, Naito, M, Kubo, M, Kamatani, Y, Shinomiya, N, Yokota, M, Wakai, K, Okada, Y & Matsuo, H 2019, 'Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals', Communications Biology, vol. 2, no. 1, 115. https://doi.org/10.1038/s42003-019-0339-0

Nakatochi, Masahiro ; Kanai, Masahiro ; Nakayama, Akiyoshi ; Hishida, Asahi ; Kawamura, Yusuke ; Ichihara, Sahoko ; Akiyama, Masato ; Ikezaki, Hiroaki ; Furusyo, Norihiro ; Shimizu, Seiko ; Yamamoto, Ken ; Hirata, Makoto ; Okada, Rieko ; Kawai, Sayo ; Kawaguchi, Makoto ; Nishida, Yuichiro ; Shimanoe, Chisato ; Ibusuki, Rie ; Takezaki, Toshiro ; Nakajima, Mayuko ; Takao, Mikiya ; Ozaki, Etsuko ; Matsui, Daisuke ; Nishiyama, Takeshi ; Suzuki, Sadao ; Takashima, Naoyuki ; Kita, Yoshikuni ; Endoh, Kaori ; Kuriki, Kiyonori ; Uemura, Hirokazu ; Arisawa, Kokichi ; Oze, Isao ; Matsuo, Keitaro ; Nakamura, Yohko ; Mikami, Haruo ; Tamura, Takashi ; Nakashima, Hiroshi ; Nakamura, Takahiro ; Kato, Norihiro ; Matsuda, Koichi ; Murakami, Yoshinori ; Matsubara, Tatsuaki ; Naito, Mariko ; Kubo, Michiaki ; Kamatani, Yoichiro ; Shinomiya, Nariyoshi ; Yokota, Mitsuhiro ; Wakai, Kenji ; Okada, Yukinori ; Matsuo, Hirotaka. / Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. In: Communications Biology. 2019 ; Vol. 2, No. 1.

@article{aec367ca7c55470d9d26fb36a4174d48,

title = "Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals",

abstract = "Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.",

author = "Masahiro Nakatochi and Masahiro Kanai and Akiyoshi Nakayama and Asahi Hishida and Yusuke Kawamura and Sahoko Ichihara and Masato Akiyama and Hiroaki Ikezaki and Norihiro Furusyo and Seiko Shimizu and Ken Yamamoto and Makoto Hirata and Rieko Okada and Sayo Kawai and Makoto Kawaguchi and Yuichiro Nishida and Chisato Shimanoe and Rie Ibusuki and Toshiro Takezaki and Mayuko Nakajima and Mikiya Takao and Etsuko Ozaki and Daisuke Matsui and Takeshi Nishiyama and Sadao Suzuki and Naoyuki Takashima and Yoshikuni Kita and Kaori Endoh and Kiyonori Kuriki and Hirokazu Uemura and Kokichi Arisawa and Isao Oze and Keitaro Matsuo and Yohko Nakamura and Haruo Mikami and Takashi Tamura and Hiroshi Nakashima and Takahiro Nakamura and Norihiro Kato and Koichi Matsuda and Yoshinori Murakami and Tatsuaki Matsubara and Mariko Naito and Michiaki Kubo and Yoichiro Kamatani and Nariyoshi Shinomiya and Mitsuhiro Yokota and Kenji Wakai and Yukinori Okada and Hirotaka Matsuo",

note = "Funding Information: We thank all subjects for their involvement in the study; staff of the institutions participating in the J-MICC Study, BBJ Project, and KING Study for their assistance in collection of samples and clinical information; Y. Mitsuda and K. Shibata (Department of Preventive Medicine, Nagoya University Graduate School of Medicine) for technical assistance; K. Gotanda, M. Miyazawa, and R. Sugiyama (National Defense Medical College) for discussion; and N. Hamajima (Nagoya University Graduate School of Medicine) for sample collection. We thank A.P. Morris for providing us with the MANTRA software. The present study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan including KAKENHI grants (nos. 25293145 and 15K15227); the Ministry of Health, Labor, and Welfare of Japan; the Ministry of Defense of Japan; the Japan Society for the Promotion of Science (JSPS); the Kawano Masanori Memorial Foundation for Promotion of Pediatrics; and the Gout Research Foundation of Japan. The KING Study was supported in part by Grants-in-Aid from MEXT (nos. 24390169, 16H05250, 25293144, 15K19242, 16H06277, and 18K06942) as well as by a grant from the Funding Program for Next-Generation World-Leading Researchers (NEXT Program, no. LS056). The J-MICC Study was supported by Grants-in-Aid for Scientific Research from MEXT, including those for Priority Areas of Cancer (no. 17015018) and Innovative Areas (no. 221S0001), as well as by a JSPS KAKENHI grant (no. 16H06277). This study was supported in part by funding from the BioBank Japan Project from the Japan Agency for Medical Research and Development, and the Ministry of Education, Culture, Sports, Science and Technology.",

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month = dec,

day = "1",

doi = "10.1038/s42003-019-0339-0",

language = "English",

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journal = "Communications Biology",

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TY - JOUR

T1 - Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

AU - Nakatochi, Masahiro

AU - Kanai, Masahiro

AU - Nakayama, Akiyoshi

AU - Hishida, Asahi

AU - Kawamura, Yusuke

AU - Ichihara, Sahoko

AU - Akiyama, Masato

AU - Ikezaki, Hiroaki

AU - Furusyo, Norihiro

AU - Shimizu, Seiko

AU - Yamamoto, Ken

AU - Hirata, Makoto

AU - Okada, Rieko

AU - Kawai, Sayo

AU - Kawaguchi, Makoto

AU - Nishida, Yuichiro

AU - Shimanoe, Chisato

AU - Ibusuki, Rie

AU - Takezaki, Toshiro

AU - Nakajima, Mayuko

AU - Takao, Mikiya

AU - Ozaki, Etsuko

AU - Matsui, Daisuke

AU - Nishiyama, Takeshi

AU - Suzuki, Sadao

AU - Takashima, Naoyuki

AU - Kita, Yoshikuni

AU - Endoh, Kaori

AU - Kuriki, Kiyonori

AU - Uemura, Hirokazu

AU - Arisawa, Kokichi

AU - Oze, Isao

AU - Matsuo, Keitaro

AU - Nakamura, Yohko

AU - Mikami, Haruo

AU - Tamura, Takashi

AU - Nakashima, Hiroshi

AU - Nakamura, Takahiro

AU - Kato, Norihiro

AU - Matsuda, Koichi

AU - Murakami, Yoshinori

AU - Matsubara, Tatsuaki

AU - Naito, Mariko

AU - Kubo, Michiaki

AU - Kamatani, Yoichiro

AU - Shinomiya, Nariyoshi

AU - Yokota, Mitsuhiro

AU - Wakai, Kenji

AU - Okada, Yukinori

AU - Matsuo, Hirotaka

N1 - Funding Information: We thank all subjects for their involvement in the study; staff of the institutions participating in the J-MICC Study, BBJ Project, and KING Study for their assistance in collection of samples and clinical information; Y. Mitsuda and K. Shibata (Department of Preventive Medicine, Nagoya University Graduate School of Medicine) for technical assistance; K. Gotanda, M. Miyazawa, and R. Sugiyama (National Defense Medical College) for discussion; and N. Hamajima (Nagoya University Graduate School of Medicine) for sample collection. We thank A.P. Morris for providing us with the MANTRA software. The present study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan including KAKENHI grants (nos. 25293145 and 15K15227); the Ministry of Health, Labor, and Welfare of Japan; the Ministry of Defense of Japan; the Japan Society for the Promotion of Science (JSPS); the Kawano Masanori Memorial Foundation for Promotion of Pediatrics; and the Gout Research Foundation of Japan. The KING Study was supported in part by Grants-in-Aid from MEXT (nos. 24390169, 16H05250, 25293144, 15K19242, 16H06277, and 18K06942) as well as by a grant from the Funding Program for Next-Generation World-Leading Researchers (NEXT Program, no. LS056). The J-MICC Study was supported by Grants-in-Aid for Scientific Research from MEXT, including those for Priority Areas of Cancer (no. 17015018) and Innovative Areas (no. 221S0001), as well as by a JSPS KAKENHI grant (no. 16H06277). This study was supported in part by funding from the BioBank Japan Project from the Japan Agency for Medical Research and Development, and the Ministry of Education, Culture, Sports, Science and Technology.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.

AB - Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.

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