Genetic variation in ataxia gene ATXN7 influences cerebellar grey matter volume in healthy adults.

An increasing number of candidate genes for common and rare brain disorders are discovered, but the mechanism of action through which these genes cause disease is often still unclear. Some of the genetic factors known to increase the risk for common brain disorders affect brain structure, even in healthy individuals, and therefore possibly have a role in the normal development of specific brain regions. In this study, we explored this principle for a group of rare brain disorders, the spinocerebellar ataxias (SCAs). As a proof of concept, we investigated whether genetic variation in a gene known to cause a polyglutamine-expansion SCA is associated with cerebellar volume in healthy adults. The functional single nucleotide polymorphism (SNP) rs3774729 located in ATXN7 was selected as the variant of interest. Cerebellar grey matter volume was determined using volumetry on magnetic resonance imaging data in a discovery sample scanned at 1.5 T (n = 680) and a replication sample scanned at 3 T (n = 683), both consisting of healthy adults aged 18 to 35 years. The volumes were compared as a function of the presence of the minor allele of SNP rs3774729, which was associated with significantly smaller cerebellar grey matter volume in both the discovery and replication sample (p = 0.033 and p = 0.024, respectively). Our results demonstrate that a common genetic variant in the ataxia-causing gene ATXN7 influences cerebellar grey matter volume in healthy young adults. This finding may also imply that genes associated with cerebellar volume in healthy subjects are valid candidates for causing or modifying ataxia.