title: A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN.
abstract: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns.
  
  
  
  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.
  
  
  
  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).
  
  
  
  We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Atsuta
authors.affiliation: Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirakawa
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakatochi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Science, RIKEN, Tokyo, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Integrative Medical Science, RIKEN, Tokyo, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Yokoi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kanai
authors.affiliation: Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Taniguchi
authors.affiliation: Department of Neurology, National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Aiba
authors.affiliation: Department of Neurology, Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Neurology, National Hospital Organization, Shizuoka-Fuji National Hospital, Fujinomiya, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizoguchi
authors.affiliation: Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Oda
authors.affiliation: Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kano
authors.affiliation: Department of Neurology, Geriatrics Research Institute, Maebashi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Satoshi
authors.identifier: 0000-0002-4716-8578
authors.initials: S
authors.lastname: Kuwabara
authors.affiliation: Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Division of Neurology, National Hospital Organization, Miyagi National Hospital, Miyagi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
authors.affiliation: Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawata
authors.affiliation: Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics*; D064211:Connectin / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis
chemical_list: D064211:Connectin; C577285:TTN protein, human