A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. Issue 8 (8th January 2016)

• Record Type: Journal Article
• Authors: 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;
• Other Names: Yuasa Tatsuhiko author non-byline.; Kano Takahiro author non-byline.; Sasaki Hidenao author non-byline.; Kato Masaaki author non-byline.; Imai Takashi author non-byline.; Ishihara Tomohiko author non-byline.; Nishizawa Masatoyo author non-byline.; Fujita Yukio author non-byline.; Ikeda Masaki author non-byline.; Shibuya Kazumoto author non-byline.; Hayashi Hideaki author non-byline.; Takahashi Yuji author non-byline.; Murata Miho author non-byline.; Ishiura Hiroyuki author non-byline.; Ogaki Kotaro author non-byline.; Hattori Nobutaka author non-byline.; Tomiyama Hiroyuki author non-byline.; Aizawa Hitoshi author non-byline.; Nakamura Mie author non-byline.; Iwasaki Yasuo author non-byline.; Nagasaka Takamura author non-byline.; Takiyama Yoshihisa author non-byline.; Obi Tomokazu author non-byline.; Sakai Motoko author non-byline.; Konagaya Masaaki author non-byline.; Noto Yu-ichi author non-byline.; Nakagawa Masanori author non-byline.; Yamashita Hirofumi author non-byline.; Takahashi Ryosuke author non-byline.; Fujita Takuji author non-byline.; Yamashita Toru author non-byline.; Hiji Masanori author non-byline.; Watanabe Yasuhiro author non-byline.; Hayashi Shintaro author non-byline.; Kira Jun-ichi author non-byline.;
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 87:Issue 8(2016)
• Page Start: 851
• Page End: 858
• Publication Date: 2016-01-08
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2015-311541
• Languages: English
• ISSNs: 0022-3050

Abstract

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 .