C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

Ji He, Lu Tang, Beben Benyamin, Sonia Shah, Gib Hemani, Rong Liu, Shan Ye, Xiaolu Liu, Yan Ma, Huagang Zhang, Katie Cremin, Paul Leo, Naomi R. Wray, Peter M. Visscher, Huji Xu, Matthew A. Brown, Perry F. Bartlett, Marie Mangelsdorf, Dongsheng Fan

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

LanguageEnglish
Pages2660.e1-2660.e8
JournalNeurobiology of Aging
Volume36
Issue number9
DOIs
Publication statusPublished - 1 Sep 2015

Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72 gene
  • Chinese population
  • CpG methylation
  • Hexanucleotide repeat expansion

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

He, Ji ; Tang, Lu ; Benyamin, Beben ; Shah, Sonia ; Hemani, Gib ; Liu, Rong ; Ye, Shan ; Liu, Xiaolu ; Ma, Yan ; Zhang, Huagang ; Cremin, Katie ; Leo, Paul ; Wray, Naomi R. ; Visscher, Peter M. ; Xu, Huji ; Brown, Matthew A. ; Bartlett, Perry F. ; Mangelsdorf, Marie ; Fan, Dongsheng. / C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis. In: Neurobiology of Aging. 2015 ; Vol. 36, No. 9. pp. 2660.e1-2660.e8.
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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.",
keywords = "Amyotrophic lateral sclerosis, C9orf72 gene, Chinese population, CpG methylation, Hexanucleotide repeat expansion",
author = "Ji He and Lu Tang and Beben Benyamin and Sonia Shah and Gib Hemani and Rong Liu and Shan Ye and Xiaolu Liu and Yan Ma and Huagang Zhang and Katie Cremin and Paul Leo and Wray, {Naomi R.} and Visscher, {Peter M.} and Huji Xu and Brown, {Matthew A.} and Bartlett, {Perry F.} and Marie Mangelsdorf and Dongsheng Fan",
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He, J, Tang, L, Benyamin, B, Shah, S, Hemani, G, Liu, R, Ye, S, Liu, X, Ma, Y, Zhang, H, Cremin, K, Leo, P, Wray, NR, Visscher, PM, Xu, H, Brown, MA, Bartlett, PF, Mangelsdorf, M & Fan, D 2015, 'C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis', Neurobiology of Aging, vol. 36, no. 9, pp. 2660.e1-2660.e8. https://doi.org/10.1016/j.neurobiolaging.2015.06.002

C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis. / He, Ji; Tang, Lu; Benyamin, Beben; Shah, Sonia; Hemani, Gib; Liu, Rong; Ye, Shan; Liu, Xiaolu; Ma, Yan; Zhang, Huagang; Cremin, Katie; Leo, Paul; Wray, Naomi R.; Visscher, Peter M.; Xu, Huji; Brown, Matthew A.; Bartlett, Perry F.; Mangelsdorf, Marie; Fan, Dongsheng.

In: Neurobiology of Aging, Vol. 36, No. 9, 01.09.2015, p. 2660.e1-2660.e8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

AU - He, Ji

AU - Tang, Lu

AU - Benyamin, Beben

AU - Shah, Sonia

AU - Hemani, Gib

AU - Liu, Rong

AU - Ye, Shan

AU - Liu, Xiaolu

AU - Ma, Yan

AU - Zhang, Huagang

AU - Cremin, Katie

AU - Leo, Paul

AU - Wray, Naomi R.

AU - Visscher, Peter M.

AU - Xu, Huji

AU - Brown, Matthew A.

AU - Bartlett, Perry F.

AU - Mangelsdorf, Marie

AU - Fan, Dongsheng

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - C9orf72 gene

KW - Chinese population

KW - CpG methylation

KW - Hexanucleotide repeat expansion

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U2 - 10.1016/j.neurobiolaging.2015.06.002

DO - 10.1016/j.neurobiolaging.2015.06.002

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SP - 2660.e1-2660.e8

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T2 - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

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