• 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, Masaya Oda, Osamu Kano, Koichi Okamoto, Satoshi Kuwabara, Kazuko Hasegawa, Takashi Imai, Akihiro Kawata, Masashi Aoki, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, and Gen Sobue.
• Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
• J. Neurol. Neurosurg. Psychiatr. 2016 Aug 1; 87 (8): 851-8.

ObjectiveTo classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns.MethodsWe 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.ResultsWe 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).ConclusionsWe detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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