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, Genki Tohnai, Masahiro Nakatochi, Naoki Atsuta, Hirohisa Watanabe, Daisuke Ito, Masahisa Katsuno, Akihiro Hirakawa, Yuishin Izumi, Mitsuya Morita, Takehisa Hirayama, Osamu Kano, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Naoki Suzuki, Masashi Aoki, Ikuko Iwata, Ichiro Yabe, Kazumoto ShibuyaSatoshi Kuwabara, Masaya Oda, Rina Hashimoto, Ikuko Aiba, Tomohiko Ishihara, Osamu Onodera, Toru Yamashita, Koji Abe, Kouichi Mizoguchi, Toshio Shimizu, Yoshio Ikeda, Takanori Yokota, Kazuko Hasegawa, Fumiaki Tanaka, Kenji Nakashima, Ryuji Kaji, Jun Ichi Niwa, Manabu Doyu, Chikashi Terao, Shiro Ikegawa, Koki Fujimori, Shiho Nakamura, Fumiko Ozawa, Satoru Morimoto, Kazunari Onodera, Takuji Ito, Yohei Okada, Hideyuki Okano, Gen Sobue

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)816-824
Number of pages9
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume94
Issue number10
DOIs
Publication statusPublished - 01-10-2023

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

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