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

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<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 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.

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Journal
Communications Biology
Published
2025-12-05
DOI
https://doi.org/10.1038/s42003-025-09168-4
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Kazumoto Shibuya, Genki Tohnai, Ichiro Yabe, Hiroyuki Ishiura et al.
Communications Biology
Amyotrophic Lateral Sclerosis Research
article

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

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

Abstract

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<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 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.

Communications BiologyVol. 8(1)
Toho University (JP), Fukushima Medical University (JP), Fujita Health University (JP), Jichi Medical University (JP), Chiba University (JP), Okayama University (JP), Aichi Medical University (JP), Gunma University (JP), Mie University (JP), Tohoku University (JP), Keio University (JP), Hokkaido University (JP), Juntendo University (JP), Kyoto Prefectural University of Medicine (JP), National Sagamihara Hospital (JP), Tokyo Metropolitan Neurological Hospital (JP), Tokyo Metropolitan Institute of Gerontology (JP), Peptide Institute (Japan) (JP), Higashi Nagoya National Hospital (JP), Nagoya University (JP), Niigata University (JP), Yokohama City University (JP), Tokushima University (JP)
Japan Agency for Medical Research and Development, Hori Sciences and Arts Foundation, Japan Society for the Promotion of Science
Openalex Percentile: Top 47%
Amyotrophic Lateral Sclerosis Research
DOIOpen Access PDFOpenAlex
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