Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Ryoichi Nakamura^#^{1

2}, Genki Tohnai^#^{2

3}, Masahiro Nakatochi^#⁴, Naoki Atsuta^{1

2}, Hirohisa Watanabe^{5

6}, Daisuke Ito², Masahisa Katsuno^{2

7}, Akihiro Hirakawa⁸, Yuishin Izumi⁹, Mitsuya Morita¹⁰, Takehisa Hirayama¹¹, Osamu Kano¹¹, Kazuaki Kanai^{12

13}, Nobutaka Hattori¹³, Akira Taniguchi¹⁴, Naoki Suzuki¹⁵, Masashi Aoki¹⁵, Ikuko Iwata¹⁶, Ichiro Yabe¹⁶, Kazumoto Shibuya¹⁷, Satoshi Kuwabara¹⁷, Masaya Oda¹⁸, Rina Hashimoto¹⁹, Ikuko Aiba¹⁹, Tomohiko Ishihara²⁰, Osamu Onodera²⁰, Toru Yamashita²¹, Koji Abe²¹, Kouichi Mizoguchi²², Toshio Shimizu²³, Yoshio Ikeda²⁴, Takanori Yokota²⁵, Kazuko Hasegawa²⁶, Fumiaki Tanaka²⁷, Kenji Nakashima²⁸, Ryuji Kaji⁹, Jun-Ichi Niwa¹, Manabu Doyu¹, Chikashi Terao²⁹, Shiro Ikegawa³⁰, Koki Fujimori³¹, Shiho Nakamura³¹, Fumiko Ozawa³¹, Satoru Morimoto³¹, Kazunari Onodera¹, Takuji Ito¹, Yohei Okada¹, Hideyuki Okano³¹, Gen Sobue^{32

33}; Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS) study group

Affiliations

¹ Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
² Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
³ Division of ALS Research, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
⁴ Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁵ Department of Neurology, Fujita Health University, Toyoake, Aichi, Japan.
⁶ Brain and Mind Research Center, Nagoya University, Nagoya, Aichi, Japan.
⁷ Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁸ Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
⁹ Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
¹⁰ Division of Neurology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
¹¹ Department of Neurology, Toho University Faculty of Medicine, Ota-ku, Tokyo, Japan.
¹² Department of Neurology, Fukushima Medical University School of Medicine, Fukushima, Japan.
¹³ Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
¹⁴ Department of Neurology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
¹⁵ Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
¹⁶ Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
¹⁷ Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
¹⁸ Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Hiroshima, Japan.
¹⁹ Department of Neurology, National Hospital Organization Higashinagoya National Hospital, Nagoya, Aichi, Japan.
²⁰ Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
²¹ Department of Neurology, Okayama University Graduate School of Medicine, Okayama, Japan.
²² Department of Neurology, National Hospital Organization Shizuoka Medical Center, Shizuoka, Japan.
²³ Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan.
²⁴ Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
²⁵ Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
²⁶ Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.
²⁷ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
²⁸ Department of Neurology, National Hospital Organization, Matsue Medical Center, Matsue, Shimane, Japan.
²⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
³⁰ Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
³¹ Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
³² Brain and Mind Research Center, Nagoya University, Nagoya, Aichi, Japan sobueg@med.nagoya-u.ac.jp.
³³ Aichi Medical University, Nagakute, Aichi, Japan.

^# Contributed equally.

PMID: 37142397
DOI: 10.1136/jnnp-2022-330851

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Ryoichi Nakamura et al. J Neurol Neurosurg Psychiatry. 2023 Oct.

. 2023 Oct;94(10):816-824.

doi: 10.1136/jnnp-2022-330851. Epub 2023 May 4.

Authors

Affiliations

¹ Department of Neurology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
² Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
³ Division of ALS Research, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
⁴ Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁵ Department of Neurology, Fujita Health University, Toyoake, Aichi, Japan.
⁶ Brain and Mind Research Center, Nagoya University, Nagoya, Aichi, Japan.
⁷ Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁸ Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
⁹ Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
¹⁰ Division of Neurology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
¹¹ Department of Neurology, Toho University Faculty of Medicine, Ota-ku, Tokyo, Japan.
¹² Department of Neurology, Fukushima Medical University School of Medicine, Fukushima, Japan.
¹³ Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
¹⁴ Department of Neurology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
¹⁵ Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
¹⁶ Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
¹⁷ Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
¹⁸ Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Hiroshima, Japan.
¹⁹ Department of Neurology, National Hospital Organization Higashinagoya National Hospital, Nagoya, Aichi, Japan.
²⁰ Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
²¹ Department of Neurology, Okayama University Graduate School of Medicine, Okayama, Japan.
²² Department of Neurology, National Hospital Organization Shizuoka Medical Center, Shizuoka, Japan.
²³ Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan.
²⁴ Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
²⁵ Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
²⁶ Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.
²⁷ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
²⁸ Department of Neurology, National Hospital Organization, Matsue Medical Center, Matsue, Shimane, Japan.
²⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
³⁰ Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
³¹ Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
³² Brain and Mind Research Center, Nagoya University, Nagoya, Aichi, Japan sobueg@med.nagoya-u.ac.jp.
³³ Aichi Medical University, Nagakute, Aichi, Japan.

^# Contributed equally.

PMID: 37142397
DOI: 10.1136/jnnp-2022-330851

Abstract

Background: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS.

Methods: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS.

Results: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10^-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10^-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10^-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression.

Conclusions: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

Keywords: ALS; genetics; motor neuron disease; neurogenetics.

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Conflict of interest statement

Competing interests: YO is a scientific adviser of Kohjin-Bio. HO is a founding scientist of SanBio.

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Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Affiliations

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

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Medical

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