Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

“…The number of CAG repeats in normal chromosomes is significantly higher in populations presenting high prevalence of HD Squitieri et al, 1994). Higher averages of CAG numbers in normal chromosomes were found in Mexico, Cuba, Brazil, Europe, North America, and Oceania (Raskin et al, 2000;Wexler et al, 2004;McNicoll et al, 2008;Alonso et al, 2009;Semaka et al, 2013b;Vázquez-Mojena et al, 2013).…”

Juvenile Huntington disease in Argentina

“…Classically, age at onset was established on the basis of 'score equal to 4', according to the DCL of the United Huntington' s Disease Rating Scale (UHDRS) in a mutation carrier subject 19 . Nevertheless, several reports on pre-manifest subjects remarked the occurrence of non-motor behavioral and cognitive manifestations anticipating the typical motor signs and symptoms by even many years 19,20,21,22,23 , thus making the definition of age at onset in JHD still controversial 5,6,19,20,21,22,23 . Recently, Reilmann et al, suggested to take in account the whole individual medical history, i.e.…”

“…Nevertheless, we believe that this series may contribute to the expansion of knowledge of the JHD variant, which is already rare and, particularly so, due to the limited number of reports focusing on this topic from South America, with the exception of the Venezuelan community 23 .…”

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

“…The expansion length is variable and explains much of the heterogeneity in the age at which mutation‐carriers receive a clinical diagnosis of manifest disease (Duyao et al, 1993). A large portion of variability in age at onset, however, remains unexplained by the gene‐mutation and is likely the result of other factors, both genetic and environmental (Wexler et al, 2004). Identifying these factors and their associated biological processes could provide additional targets for therapeutic interventions that may modify disease progression.…”