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J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):851-8. doi: 10.1136/jnnp-2015-311541. Epub 2016 Jan 8.

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

Author information

1
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
3
Laboratory for Bone and Joint Diseases, Center for Integrative Medical Science, RIKEN, Tokyo, Japan.
4
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
5
Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
6
Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.
7
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
8
Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan.
9
Department of Neurology, National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan.
10
Department of Neurology, Okayama University Graduate School of Medicine, Okayama, Japan.
11
Department of Neurology, National Hospital Organization, Shizuoka-Fuji National Hospital, Fujinomiya, Japan.
12
Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Japan.
13
Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan.
14
Department of Neurology, Geriatrics Research Institute, Maebashi, Japan.
15
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
16
Division of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan.
17
Division of Neurology, National Hospital Organization, Miyagi National Hospital, Miyagi, Japan.
18
Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
19
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
20
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
21
Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.

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.

PMID:
26746183
DOI:
10.1136/jnnp-2015-311541
[Indexed for MEDLINE]

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