A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Ryoichi Nakamura; Kazuharu Misawa; Genki Tohnai; Masahiro Nakatochi; Sho Furuhashi; Naoki Atsuta; Naoki Hayashi; Daichi Yokoi; Hazuki Watanabe; Hirohisa Watanabe; Masahisa Katsuno; Yuishin Izumi; Kazuaki Kanai; Nobutaka Hattori; Mitsuya Morita; Akira Taniguchi; Osamu Kano; Masaya Oda; Kazumoto Shibuya; Satoshi Kuwabara; Naoki Suzuki; Masashi Aoki; Yasuyuki Ohta; Toru Yamashita; Koji Abe; Rina Hashimoto; Ikuko Aiba; Koichi Okamoto; Kouichi Mizoguchi; Kazuko Hasegawa; Yohei Okada; Tomohiko Ishihara; Osamu Onodera; Kenji Nakashima; Ryuji Kaji; Yoichiro Kamatani; Shiro Ikegawa; Yukihide Momozawa; Michiaki Kubo; Noriko Ishida; Naoko Minegishi; Masao Nagasaki; Gen Sobue

doi:10.1038/s42003-020-01251-2

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi KuwabaraNaoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

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27 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10⁻⁸). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10⁻⁴). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10⁻¹¹). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

Original language	English
Article number	526
Journal	Communications Biology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-01251-2
Publication status	Published - 2020 Dec 1

ASJC Scopus subject areas

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

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10.1038/s42003-020-01251-2

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Nakamura, R., Misawa, K., Tohnai, G., Nakatochi, M., Furuhashi, S., Atsuta, N., Hayashi, N., Yokoi, D., Watanabe, H., Watanabe, H., Katsuno, M., Izumi, Y., Kanai, K., Hattori, N., Morita, M., Taniguchi, A., Kano, O., Oda, M., Shibuya, K., ... Sobue, G. (2020). A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. Communications Biology, 3(1), [526]. https://doi.org/10.1038/s42003-020-01251-2

Nakamura, R, Misawa, K, Tohnai, G, Nakatochi, M, Furuhashi, S, Atsuta, N, Hayashi, N, Yokoi, D, Watanabe, H, Watanabe, H, Katsuno, M, Izumi, Y, Kanai, K, Hattori, N, Morita, M, Taniguchi, A, Kano, O, Oda, M, Shibuya, K, Kuwabara, S, Suzuki, N , Aoki, M, Ohta, Y, Yamashita, T, Abe, K, Hashimoto, R, Aiba, I, Okamoto, K, Mizoguchi, K, Hasegawa, K, Okada, Y, Ishihara, T, Onodera, O, Nakashima, K, Kaji, R, Kamatani, Y, Ikegawa, S, Momozawa, Y, Kubo, M, Ishida, N, Minegishi, N, Nagasaki, M & Sobue, G 2020, 'A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis', Communications Biology, vol. 3, no. 1, 526. https://doi.org/10.1038/s42003-020-01251-2

@article{9e735024a32c49259ee934fb7f2d2bb5,

title = "A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis",

abstract = "Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.",

author = "Ryoichi Nakamura and Kazuharu Misawa and Genki Tohnai and Masahiro Nakatochi and Sho Furuhashi and Naoki Atsuta and Naoki Hayashi and Daichi Yokoi and Hazuki Watanabe and Hirohisa Watanabe and Masahisa Katsuno and Yuishin Izumi and Kazuaki Kanai and Nobutaka Hattori and Mitsuya Morita and Akira Taniguchi and Osamu Kano and Masaya Oda and Kazumoto Shibuya and Satoshi Kuwabara and Naoki Suzuki and Masashi Aoki and Yasuyuki Ohta and Toru Yamashita and Koji Abe and Rina Hashimoto and Ikuko Aiba and Koichi Okamoto and Kouichi Mizoguchi and Kazuko Hasegawa and Yohei Okada and Tomohiko Ishihara and Osamu Onodera and Kenji Nakashima and Ryuji Kaji and Yoichiro Kamatani and Shiro Ikegawa and Yukihide Momozawa and Michiaki Kubo and Noriko Ishida and Naoko Minegishi and Masao Nagasaki and Gen Sobue",

note = "Funding Information: The authors thank all of the ALS patients who participated in this study. The authors also thank all of the participating doctors and staff of the Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS). The participating doctors of JaCALS are listed in the Supplementary Material. This study was mainly supported by the Japan Agency for Medical Research and Development (AMED; grant numbers JP19ek0109284h0003, JP19lk1601002h0002, JP19ak0101111h0001, JP20ek0109492h0001, JP20ak0101111h0002, and JP20dm0107059h0005). This work was also partially supported by AMED (grant numbers JP17km0105001, JP17km0105002, JP17km0105003, JP17km0105004, and JP17km0405205), and by Grants-in Aid for Scientific Research (C) KAKENHI (grant numbers JP19K06523 and JP19K07973) from the Japan Society for the Promotion of Science (JSPS). A part of the computational resources was provided by the Tohoku University Tohoku Medical Megabank Organization supercomputer system (http://sc.megabank.tohoku.ac.jp/en). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s42003-020-01251-2",

language = "English",

volume = "3",

journal = "Communications Biology",

issn = "2399-3642",

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TY - JOUR

T1 - A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

AU - Nakamura, Ryoichi

AU - Misawa, Kazuharu

AU - Tohnai, Genki

AU - Nakatochi, Masahiro

AU - Furuhashi, Sho

AU - Atsuta, Naoki

AU - Hayashi, Naoki

AU - Yokoi, Daichi

AU - Watanabe, Hazuki

AU - Watanabe, Hirohisa

AU - Katsuno, Masahisa

AU - Izumi, Yuishin

AU - Kanai, Kazuaki

AU - Hattori, Nobutaka

AU - Morita, Mitsuya

AU - Taniguchi, Akira

AU - Kano, Osamu

AU - Oda, Masaya

AU - Shibuya, Kazumoto

AU - Kuwabara, Satoshi

AU - Suzuki, Naoki

AU - Aoki, Masashi

AU - Ohta, Yasuyuki

AU - Yamashita, Toru

AU - Abe, Koji

AU - Hashimoto, Rina

AU - Aiba, Ikuko

AU - Okamoto, Koichi

AU - Mizoguchi, Kouichi

AU - Hasegawa, Kazuko

AU - Okada, Yohei

AU - Ishihara, Tomohiko

AU - Onodera, Osamu

AU - Nakashima, Kenji

AU - Kaji, Ryuji

AU - Kamatani, Yoichiro

AU - Ikegawa, Shiro

AU - Momozawa, Yukihide

AU - Kubo, Michiaki

AU - Ishida, Noriko

AU - Minegishi, Naoko

AU - Nagasaki, Masao

AU - Sobue, Gen

N1 - Funding Information: The authors thank all of the ALS patients who participated in this study. The authors also thank all of the participating doctors and staff of the Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS). The participating doctors of JaCALS are listed in the Supplementary Material. This study was mainly supported by the Japan Agency for Medical Research and Development (AMED; grant numbers JP19ek0109284h0003, JP19lk1601002h0002, JP19ak0101111h0001, JP20ek0109492h0001, JP20ak0101111h0002, and JP20dm0107059h0005). This work was also partially supported by AMED (grant numbers JP17km0105001, JP17km0105002, JP17km0105003, JP17km0105004, and JP17km0405205), and by Grants-in Aid for Scientific Research (C) KAKENHI (grant numbers JP19K06523 and JP19K07973) from the Japan Society for the Promotion of Science (JSPS). A part of the computational resources was provided by the Tohoku University Tohoku Medical Megabank Organization supercomputer system (http://sc.megabank.tohoku.ac.jp/en). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

AB - Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

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U2 - 10.1038/s42003-020-01251-2

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VL - 3

JO - Communications Biology

JF - Communications Biology

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ER -

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

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