Dataset Information

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.

ABSTRACT: Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.

SUBMITTER: Tezenas du Montcel S

PROVIDER: S-EPMC4132646 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.

Tezenas du Montcel Sophie S Durr Alexandra A Bauer Peter P Figueroa Karla P KP Ichikawa Yaeko Y Brussino Alessandro A Forlani Sylvie S Rakowicz Maria M Schöls Ludger L Mariotti Caterina C van de Warrenburg Bart P C BP Orsi Laura L Giunti Paola P Filla Alessandro A Szymanski Sandra S Klockgether Thomas T Berciano José J Pandolfo Massimo M Boesch Sylvia S Melegh Bela B Timmann Dagmar D Mandich Paola P Camuzat Agnès A Goto Jun J Ashizawa Tetsuo T Cazeneuve Cécile C Tsuji Shoji S Pulst Stefan-M SM Brusco Alfredo A Riess Olaf O Brice Alexis A Stevanin Giovanni G

Brain : a journal of neurology 20140626 Pt 9

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determ ...[more]

PMID: 24972706

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Project description:ImportanceRepeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometimes referred to as intermediate) have been identified as modifiers of amyotrophic lateral sclerosis (ALS) risk. Prior studies have used thresholding considering various cutoffs for ATXN2 repeat length.ObjectiveTo calculate association between ATXN2 CAG repeat alleles and increased risk of ALS across multiple ethnic groups.Data sourcesThe MEDLINE database was searched for studies published by December 29, 2013, reporting ATXN2 CAG repeat length in patients with ALS and controls.Study selectionStudies were included if they reported original data on relative risks or odds ratios (ORs) from ALS and control populations for individual ATXN2 alleles. Review articles that reported no new data were not included in the analysis.Data extraction and synthesisAnalysis of allele distribution was performed to ensure that all studies followed identical allele sizing. The ORs, 95% confidence intervals, and population attributable risk percentages were calculated according to standard procedures.Main outcomes and measuresOccurrence of ALS associated with ATXN2 repeat alleles, expressed as ORs.ResultsNine studies were analyzed, including 7505 controls and 6151 sporadic ALS cases. The ALS and control cohorts were recruited from different geographical and ethnic regions including the United States, French Canada/Canada, Belgium and the Netherlands, Germany, Italy, mainland China, Turkey, and Flanders-Belgium. The ATXN2 CAG repeat lengths ranged from 13 to 39 in patients with ALS and from 13 to 34 in controls. The ORs were less than 1.00 for alleles with 25 to 28 repeats. The OR was 1.55 for 30 repeats, but this elevation was not statistically significant (95% CI, 0.88-2.73). The ORs were 2.70 (95% CI, 1.47-4.93) for 31 CAG repeats, 11.09 (95% CI, 4.16-29.57) for 32 repeats, and 5.76 (95% CI, 1.79-18.57) for 33 repeats.Conclusions and relevanceIn contrast to prior studies with smaller numbers, risk for ALS associated with long-normal alleles is complex. Alleles with 27 and 28 repeats lower ALS risk slightly. The risk for ALS increases beginning with 29 repeats and reaches a maximum at 32 and 33 repeats. Of note, alleles with repeats of these lengths are known to be predisposed to meiotic expansion to full-penetrance mutant alleles. In patients with ALS, alleles with 31 to 33 repeats may have undergone preferential expansion in motor neurons during mitosis or DNA repair. Our meta-analysis provides a framework for counseling individuals with long-normal ATXN2 repeats.

Dataset Information

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.

Publications

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.

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