title: C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis.
abstract: A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p < 10(-8)) or controls. The detailed analysis of the C9orf72 locus in a large cohort of Chinese samples provides robust evidence that may not be consistent with a single Caucasian founder event. Both the Caucasian and Chinese haplotypes associated with HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length.
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China; Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors.forename: Ji
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Tang
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Beben
authors.initials: B
authors.lastname: Benyamin
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors.forename: Gib
authors.initials: G
authors.lastname: Hemani
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China.
authors.forename: Huagang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors.forename: Katie
authors.initials: K
authors.lastname: Cremin
authors.affiliation: Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Leo
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Huji
authors.initials: H
authors.lastname: Xu
authors.affiliation: Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Perry F
authors.initials: PF
authors.lastname: Bartlett
authors.affiliation: Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Mangelsdorf
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China. Electronic address: dsfan2010@aliyun.com.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Fan
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: Amyotrophic lateral sclerosis; C9orf72 gene; Chinese population; CpG methylation; Hexanucleotide repeat expansion