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Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations

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Abstract

Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of “large normal alleles” defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.

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Acknowledgements

We thank all the patients for participating in this study. We also thank all the neurologists who provided samples for this study.

Funding

This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas Nos. 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid [H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080] from the Ministry of Health, Welfare and Labour, Japan, and grants (Nos. 15ek0109065h0002, 16kk0205001h001, 17kk0205001h0002, and 17ek0109279h0001) from the Japan Agency for Medical Research and Development (AMED) to S.T.

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Authors and Affiliations

  1. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Hiroya Naruse, Takashi Matsukawa, Hiroyuki Ishiura, Jun Mitsui & Tatsushi Toda

  2. Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan

    Takashi Matsukawa, Jun Mitsui & Shoji Tsuji

  3. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yuji Takahashi

  4. Department of Neurology, Tachikawa General Hospital, Niigata, Japan

    Hiroki Takano

  5. Department of Neurology, International University of Health and Welfare Mita Hospital, Tokyo, Japan

    Jun Goto

  6. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan

    Shoji Tsuji

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Correspondence to Shoji Tsuji.

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Genomic DNA samples were obtained from all the participants with their written informed consent, and this research was approved by the institutional review board of the University of Tokyo.

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Supplementary Fig. 1

Forest plot showing the result of the meta-analysis combining the frequencies of ALS risk alleles (CAG repeat units >29) in the previous studies from various ethnic populations and the present study. (PPTX 51 kb)

Supplementary Table 1.

Distribution of number of CAG/CAA repeat units in ALS and control individuals in various populations (DOC 79 kb).

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Naruse, H., Matsukawa, T., Ishiura, H. et al. Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations. Neurogenetics 20, 65–71 (2019). https://doi.org/10.1007/s10048-019-00570-9

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