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Research paper
A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN
  1. Hazuki Watanabe1,
  2. Naoki Atsuta1,
  3. Akihiro Hirakawa2,
  4. Ryoichi Nakamura1,
  5. Masahiro Nakatochi2,
  6. Shinsuke Ishigaki1,
  7. Aritoshi Iida3,
  8. Shiro Ikegawa3,
  9. Michiaki Kubo4,
  10. Daichi Yokoi1,
  11. Hirohisa Watanabe1,
  12. Mizuki Ito1,
  13. Masahisa Katsuno1,
  14. Yuishin Izumi5,
  15. Mitsuya Morita6,
  16. Kazuaki Kanai7,
  17. Akira Taniguchi8,
  18. Ikuko Aiba9,
  19. Koji Abe10,
  20. Koichi Mizoguchi11,
  21. Masaya Oda12,
  22. Osamu Kano13,
  23. Koichi Okamoto14,
  24. Satoshi Kuwabara15,
  25. Kazuko Hasegawa16,
  26. Takashi Imai17,
  27. Akihiro Kawata18,
  28. Masashi Aoki19,
  29. Shoji Tsuji20,
  30. Kenji Nakashima21,
  31. Ryuji Kaji5,
  32. Gen Sobue1
    1. 1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
    2. 2Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
    3. 3Laboratory for Bone and Joint Diseases, Center for Integrative Medical Science, RIKEN, Tokyo, Japan
    4. 4Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
    5. 5Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
    6. 6Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
    7. 7Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    8. 8Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan
    9. 9Department of Neurology, National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan
    10. 10Department of Neurology, Okayama University Graduate School of Medicine, Okayama, Japan
    11. 11Department of Neurology, National Hospital Organization, Shizuoka-Fuji National Hospital, Fujinomiya, Japan
    12. 12Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Japan
    13. 13Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan
    14. 14Department of Neurology, Geriatrics Research Institute, Maebashi, Japan
    15. 15Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
    16. 16Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan
    17. 17Division of Neurology, National Hospital Organization, Miyagi National Hospital, Miyagi, Japan
    18. 18Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
    19. 19Department of Neurology, Tohoku University School of Medicine, Sendai, Japan
    20. 20Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
    21. 21Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
    1. Correspondence to Professor Gen Sobue, Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 Japan; sobueg{at}


    Objective To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns.

    Methods We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs.

    Results We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47–8.34×10−8). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10−10–1.1×10−7). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002).

    Conclusions We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

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