A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN

Hazuki Watanabe, Naoki Atsuta, Akihiro Hirakawa, Ryoichi Nakamura, Masahiro Nakatochi, Shinsuke Ishigaki, Aritoshi Iida, Shiro Ikegawa, Michiaki Kubo, Daichi Yokoi, Hirohisa Watanabe, Mizuki Ito, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Kazuaki Kanai, Akira Taniguchi, Ikuko Aiba, Koji Abe, Koichi Mizoguchi & 12 others Masaya Oda, Osamu Kano, Koichi Okamoto, Satoshi Kuwabara, Kazuko Hasegawa, Takashi Imai, Akihiro Kawata, Masashi Aoki, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Gen Sobue

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Abstract

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.

Original languageEnglish
Pages (from-to)851-858
Number of pages8
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume87
Issue number8
DOIs
Publication statusPublished - 08-01-2016
Externally publishedYes

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Amyotrophic Lateral Sclerosis
Single Nucleotide Polymorphism
Alleles
Linkage Disequilibrium
Connectin
Genetic Databases
Sarcomeres
Quantitative Trait Loci
Genome
Databases
Lymphocytes
Amyotrophic lateral sclerosis 1
Proteins

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

Watanabe, Hazuki ; Atsuta, Naoki ; Hirakawa, Akihiro ; Nakamura, Ryoichi ; Nakatochi, Masahiro ; Ishigaki, Shinsuke ; Iida, Aritoshi ; Ikegawa, Shiro ; Kubo, Michiaki ; Yokoi, Daichi ; Watanabe, Hirohisa ; Ito, Mizuki ; Katsuno, Masahisa ; Izumi, Yuishin ; Morita, Mitsuya ; Kanai, Kazuaki ; Taniguchi, Akira ; Aiba, Ikuko ; Abe, Koji ; Mizoguchi, Koichi ; Oda, Masaya ; Kano, Osamu ; Okamoto, Koichi ; Kuwabara, Satoshi ; Hasegawa, Kazuko ; Imai, Takashi ; Kawata, Akihiro ; Aoki, Masashi ; Tsuji, Shoji ; Nakashima, Kenji ; Kaji, Ryuji ; Sobue, Gen. / A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. In: Journal of Neurology, Neurosurgery and Psychiatry. 2016 ; Vol. 87, No. 8. pp. 851-858.
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abstract = "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.",
author = "Hazuki Watanabe and Naoki Atsuta and Akihiro Hirakawa and Ryoichi Nakamura and Masahiro Nakatochi and Shinsuke Ishigaki and Aritoshi Iida and Shiro Ikegawa and Michiaki Kubo and Daichi Yokoi and Hirohisa Watanabe and Mizuki Ito and Masahisa Katsuno and Yuishin Izumi and Mitsuya Morita and Kazuaki Kanai and Akira Taniguchi and Ikuko Aiba and Koji Abe and Koichi Mizoguchi and Masaya Oda and Osamu Kano and Koichi Okamoto and Satoshi Kuwabara and Kazuko Hasegawa and Takashi Imai and Akihiro Kawata and Masashi Aoki and Shoji Tsuji and Kenji Nakashima and Ryuji Kaji and Gen Sobue",
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Watanabe, H, Atsuta, N, Hirakawa, A, Nakamura, R, Nakatochi, M, Ishigaki, S, Iida, A, Ikegawa, S, Kubo, M, Yokoi, D, Watanabe, H, Ito, M, Katsuno, M, Izumi, Y, Morita, M, Kanai, K, Taniguchi, A, Aiba, I, Abe, K, Mizoguchi, K, Oda, M, Kano, O, Okamoto, K, Kuwabara, S, Hasegawa, K, Imai, T, Kawata, A, Aoki, M, Tsuji, S, Nakashima, K, Kaji, R & Sobue, G 2016, 'A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN', Journal of Neurology, Neurosurgery and Psychiatry, vol. 87, no. 8, pp. 851-858. https://doi.org/10.1136/jnnp-2015-311541

A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. / Watanabe, Hazuki; Atsuta, Naoki; Hirakawa, Akihiro; Nakamura, Ryoichi; Nakatochi, Masahiro; Ishigaki, Shinsuke; Iida, Aritoshi; Ikegawa, Shiro; Kubo, Michiaki; Yokoi, Daichi; Watanabe, Hirohisa; Ito, Mizuki; Katsuno, Masahisa; Izumi, Yuishin; Morita, Mitsuya; Kanai, Kazuaki; Taniguchi, Akira; Aiba, Ikuko; Abe, Koji; Mizoguchi, Koichi; Oda, Masaya; Kano, Osamu; Okamoto, Koichi; Kuwabara, Satoshi; Hasegawa, Kazuko; Imai, Takashi; Kawata, Akihiro; Aoki, Masashi; Tsuji, Shoji; Nakashima, Kenji; Kaji, Ryuji; Sobue, Gen.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 87, No. 8, 08.01.2016, p. 851-858.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN

AU - Watanabe, Hazuki

AU - Atsuta, Naoki

AU - Hirakawa, Akihiro

AU - Nakamura, Ryoichi

AU - Nakatochi, Masahiro

AU - Ishigaki, Shinsuke

AU - Iida, Aritoshi

AU - Ikegawa, Shiro

AU - Kubo, Michiaki

AU - Yokoi, Daichi

AU - Watanabe, Hirohisa

AU - Ito, Mizuki

AU - Katsuno, Masahisa

AU - Izumi, Yuishin

AU - Morita, Mitsuya

AU - Kanai, Kazuaki

AU - Taniguchi, Akira

AU - Aiba, Ikuko

AU - Abe, Koji

AU - Mizoguchi, Koichi

AU - Oda, Masaya

AU - Kano, Osamu

AU - Okamoto, Koichi

AU - Kuwabara, Satoshi

AU - Hasegawa, Kazuko

AU - Imai, Takashi

AU - Kawata, Akihiro

AU - Aoki, Masashi

AU - Tsuji, Shoji

AU - Nakashima, Kenji

AU - Kaji, Ryuji

AU - Sobue, Gen

PY - 2016/1/8

Y1 - 2016/1/8

N2 - 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.

AB - 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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U2 - 10.1136/jnnp-2015-311541

DO - 10.1136/jnnp-2015-311541

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JO - Journal of Neurology, Neurosurgery and Psychiatry

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