Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis

Ogaki, Kotaro; Li, Yuanzhe; Atsuta, Naoki; Tomiyama, Hiroyuki; Funayama, Manabu; Watanabe, H.; Nakamura, Ryoichi; Yoshino, Hideo; Yato, Seiji; Tamura, Asako; Naito, Yutaka; Taniguchi, Akira; Fujita, Koji; Izumi, Yuishin; Kaji, Ryuji; Hattori, Nobutaka; Sobue, Gen

doi:10.1016/j.neurobiolaging.2012.05.011

Cited by 101 publications

(64 citation statements)

References 19 publications

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“…However, the reported frequencies in Asian samples have been lower. Four studies have reported a low frequency of HRE in Japanese ALS cases (0 -3.4% in fALS, and 0.4% sALS) [73,78,129,130] and a higher frequency was reported in cases from Taiwan of Han Chinese ancestry (18.2% in fALS, and 2.0% in sALS) [75]. In the present study, the author reports that the frequency of the C9orf72 HRE in Chinese sALS patients is 0.3%.…”

Section: Discussionsupporting

confidence: 45%

“…To date, this is the largest cohort screened in non-Caucasian ALS cases. Previous reports about C9orf72 HRE in different populations support the hypothesis that the pathogenic HRE arose from a single founder haplotype both in Caucasian and Asian populations [11,73,75,78,80,81,129,130], although for cases in Taiwan it was postulated that the HRE was introduced in the 17 th century when Taiwan was under Dutch and Spanish colonial rule. The conjecture that Asian HREs arose on the same European founder seems inconsistent with the mutation occurring in a founder 1,500 years ago [78].…”

Section: Discussionmentioning

confidence: 97%

“…The reported frequencies in Asia have been lower. Two Japanese studies report that the frequencies of the repeat expansion range from 0-3.4% in fALS and 0-0.4% in sALS [73,74]. In contrast, a small study in Taiwanese of Han Chinese ancestry reported higher frequencies of the repeat expansion (18.2% in fALS patients and 2.0% in sALS patients) [75].…”

Section: C9orf72 Gene and Alsmentioning

confidence: 97%

“…Most reports about C9orf72 repeat expansion frequencies in different populations support the hypothesis that the pathogenic repeat expansion in C9orf72 arose from a single founder haplotype [11,67,80] both in Caucasian and Asian populations [73,75], as tagged by the A allele of rs3849942,which occurs in most reported C9orf72 GGGGCC repeatcarrying ALS cases and the A allele of rs2814707, which has been used as a significant genetic association marker of chromosome 9p21 in the Flanders-Belgian cohort of patients with FTLD, FTLD-ALS, and ALS (odds ratio 2.6, 95% CI 1.5-4.7; p=0.001). It has been estimated that the repeat expansion occurred once ~1,500 years ago [78].…”

Section: C9orf72 Gene and Alsmentioning

confidence: 98%

“…To date, the frequencies of the C9orf72 repeat expansions in more than 10 ALS cohorts from Caucasian populations range from 10.95% to 47% in fALS and 3.20% to 21.1% in sALS [67][68][69][70][71][72][73]. The reported frequencies in Asia have been lower.…”

Section: C9orf72 Gene and Alsmentioning

confidence: 99%

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Genetics of amyotrophic lateral sclerosis in the Han Chinese

He¹

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Amyotrophic lateral sclerosis is the most frequently occurring neuromuscular degenerative disorders, and has an obscure aetiology. Whilst major progress has been made, the majority of the genetic variation involved in ALS is, as yet, undefined. In this thesis, multiple genetic studies have been conducted to advance our understanding of the genetic architecture of the disease. In the light of the paucity of comprehensive genetic studies performed in Chinese, the presented study focused on advancing our current understanding in genetics of ALS in the Han Chinese population. To identify genetic variants altering risk of ALS, a genome-wide association study (GWAS) was performed.The study included 1,324 Chinese ALS cases and 3,115 controls. After quality control, a number of analyses were performed in a cleaned dataset of 1,243 cases and 2,854 controls that included: a genome-wide association analysis to identify SNPs associated with ALS; a genomic restricted maximum likelihood (GREML) analysis to estimate the proportion of the phenotypic variance in ALS liability due to common SNPs; and a genebased analysis to identify genes associated with ALS. There were no genome-wide significant SNPs or genes associated with ALS. However, it was estimated that 17% (SE: 0.05; P=6×10 -5 ) of the phenotypic variance in ALS liability was due to common SNPs. The top associated SNP was within GNAS (rs4812037; p =7×10 -7 ). GNAS was also the most associated gene from the gene-based study (p =2×10 -5 ). Based on GWAS data, a fragment-length and repeat-primed PCR was performed to determine GGGGCC copy number and expansion within the C9orf72 gene in the cohorts (1,092 sporadic ALS and 1,062 controls) from China.A haplotype analysis of 23 SNPs within and surrounding the C9orf72 gene was performed.The C9orf72 hexanucleotide (GGGGCC)n repeat expansion (HRE) was found in three sALS patients (0.3%) but not in control subjects (p = 0.25, Fisher's exact test). Two cases 2 with HRE did not harbor four risk alleles that have previously been determined to be Contributions by others to the thesis

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 97%

Section: C9orf72 Gene and Alsmentioning

confidence: 97%

Section: C9orf72 Gene and Alsmentioning

confidence: 98%

Section: C9orf72 Gene and Alsmentioning

confidence: 99%

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Genetics of amyotrophic lateral sclerosis in the Han Chinese

He¹

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Analysis of theC9orf72Gene in Patients with Amyotrophic Lateral Sclerosis in Spain and Different Populations Worldwide

García‐Redondo¹,

Dols‐Icardo²,

Rojas‐García³

et al. 2012

Human Mutation

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A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co‐occurrence of FTD (P = 8.2 × 10−5), and more family history of ALS (P = 1.4 × 10−20), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.

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Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database

et al. 2020

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The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well‐established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome‐wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease‐associated candidates, points to a significant enrichment for cell cycle‐ and division‐related genes. Within this network, literature text‐mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS‐related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (http://www.gendal.org).

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Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis

Cited by 101 publications

References 19 publications

Genetics of amyotrophic lateral sclerosis in the Han Chinese

Genetics of amyotrophic lateral sclerosis in the Han Chinese

Analysis of theC9orf72Gene in Patients with Amyotrophic Lateral Sclerosis in Spain and Different Populations Worldwide

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database

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