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.

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

“…Choice of statistical modelling might further evidence how populational differences in CAGexp can impact AO determination. Significant increase in explanation of AO variability was detected in Han Chinese,8 European carriers from non-Portuguese populations and Americans6 using quadratic models. Here, the quadratic modelling of CAGexp from IPDs yielded only a marginal improvement when compared with a simpler, linear regression modelling of AO variance.…”

“…IPD and AD retrieved from 11 studies comprised four cohorts from Europe,6 7 17 18 three from Asia,8 19 20 one from North America,6 one from Central America21 and three from Brazil 5 22 23. Brazilian cohorts comprised the Rio Grande do Sul (Brazil-RS) cohort23 and cohorts from other Brazilian regions (Brazil-non-RS cohorts): namely, subjects from São Paulo State22 and those described by Neurogenetics Network, a consortium of Brazilian researchers 5.…”

“…SCA3/MJD populations with larger CAGexp belonged to Brazilian and Asian cohorts. Inversely, subjects from Austria, Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain and UK (EUROSCA cohort)6 had the shortest mean CAGexp. Reasons for such differences are still unknown.…”

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

“…The Genetic Modifiers of Huntington's Disease (GeM‐HD) genome‐wide association study (GWAS)6 found two genome‐wide loci associated with age at motor onset in HD on chromosomes 15 and 8, with two independent signals at the same locus on chromosome 15. A few SCA genetic modifiers have been proposed3, 5, 7, 8, 9 and no GWAS have been reported.…”

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

“…In SCAs with (CAG)n-repeats, the negative correlation between the size of the polyglutamine expansion and the age at onset [56] only accounts for 50-70 % of its variability. A large cohort study on 1255 affected patients allowed an assessment to be made of the influence on the age at onset of the length of the normal allele in trans (SCA1, 6, 7) and of other (CAG)n-containing genes [57]. Furthermore, intermediate-size CAG repeats in ATXN2 were recently shown to be a risk factor in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia with ALS ([29 repeats [58]), and possibly in Parkinson's disease ([24 repeats [59]).…”