title: A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 × 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-β (TGF-β) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls.  Our results strongly suggest that ZNF512B is an important positive regulator of TGF-β signaling and that decreased ZNF512B expression increases susceptibility to ALS.
authors.affiliation: Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo 108-8639, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.forename: Naoya
authors.initials: N
authors.lastname: Hosono
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Oshima
authors.forename: Motoki
authors.initials: M
authors.lastname: Sano
authors.forename: Tetsumasa
authors.initials: T
authors.lastname: Kamei
authors.forename: Torao
authors.initials: T
authors.lastname: Tokuda
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizoguchi
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Morita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Naoki
authors.initials: N
authors.lastname: Atsuta
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Watanabe
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D016212:Transforming Growth Factor beta; C554937:ZNF512B protein, human