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<p>Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the <i>ADAM29</i>-<i>GPM6A</i> locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10<sup>-8</sup>); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10<sup>−9</sup>). Among 65 ALS patients with a <i>SOD1</i> mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with <i>GPM6A</i> upregulation in iPSC-derived motor neurons, suggesting <i>GPM6A</i> as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.</p>

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A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS

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  • 发表日期：

    2025年12月5日

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  • Ryoichi Nakamura,
  • Genki Tohnai,
  • Naoki Atsuta,
  • Yumi Matsuda,
  • Satoru Morimoto,
  • Daisuke Ito,
  • Masahisa Katsuno,
  • Yuishin Izumi,
  • Mitsuya Morita,
  • Ikuko Iwata,
  • Ichiro Yabe,
  • Tomoko Nakazato,
  • Nobutaka Hattori,
  • Takehisa Hirayama,
  • Osamu Kano,
  • Asako Tamura,
  • Naoki Suzuki,
  • Masashi Aoki,
  • Kazumoto Shibuya,
  • Satoshi Kuwabara,
  • Masaya Oda,
  • Rina Hashimoto,
  • Ikuko Aiba,
  • Tomohiko Ishihara,
  • Osamu Onodera,
  • Toru Yamashita,
  • Hiroyuki Ishiura,
  • Kota Bokuda,
  • Toshio Shimizu,
  • Yoshio Ikeda,
  • Kazuko Hasegawa,
  • Fumiaki Tanaka,
  • Takanori Yokota,
  • Kazuaki Kanai,
  • Yu-ichi Noto,
  • Ryuji Kaji,
  • Hirohisa Watanabe,
  • Tomoko Konishi,
  • Mikiko Hasegawa,
  • Hozuki Fukaya,
  • Jun-ichi Niwa,
  • Manabu Doyu,
  • Yohei Okada,
  • Shiho Nakamura,
  • Fumiko Ozawa,
  • Hideyuki Okano,
  • Masahiro Nakatochi,
  • Gen Sobue

摘要

Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10−9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.