PT  - JOURNAL ARTICLE
AU  - Hazuki Watanabe
AU  - Naoki Atsuta
AU  - Akihiro Hirakawa
AU  - Ryoichi Nakamura
AU  - Masahiro Nakatochi
AU  - Shinsuke Ishigaki
AU  - Aritoshi Iida
AU  - Shiro Ikegawa
AU  - Michiaki Kubo
AU  - Daichi Yokoi
AU  - Hirohisa Watanabe
AU  - Mizuki Ito
AU  - Masahisa Katsuno
AU  - Yuishin Izumi
AU  - Mitsuya Morita
AU  - Kazuaki Kanai
AU  - Akira Taniguchi
AU  - Ikuko Aiba
AU  - Koji Abe
AU  - Koichi Mizoguchi
AU  - Masaya Oda
AU  - Osamu Kano
AU  - Koichi Okamoto
AU  - Satoshi Kuwabara
AU  - Kazuko Hasegawa
AU  - Takashi Imai
AU  - Akihiro Kawata
AU  - Masashi Aoki
AU  - Shoji Tsuji
AU  - Kenji Nakashima
AU  - Ryuji Kaji
AU  - Gen Sobue
TI  - A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of <em>TTN</em>
AID  - 10.1136/jnnp-2015-311541
DP  - 2016 Aug 01
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - 851--858
VI  - 87
IP  - 8
4099  - http://jnnp.bmj.com/content/87/8/851.short
4100  - http://jnnp.bmj.com/content/87/8/851.full
SO  - J Neurol Neurosurg Psychiatry2016 Aug 01; 87
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.