Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Abstract

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R² = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10^-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.

Keywords: ATXN3; GWAS; Machado-Joseph disease; age at onset; modifier.

Figure 1

The inverse correlation between CAG_exp and AO (left) and the distribution of residual AO (right) observed in our MJD cohort.

Figure 2

Manhattan plot of the GWAS for residual AO of MJD. Imputed using the HRC panel, 6,716,580 variants that passed QC are included in the plot. The x-axis shows the physical position along the genome. The y-axis shows the −log₁₀(p-value) for association. The red line indicates the level of genome-wide suggestive association (P = 1 × 10⁻⁵).

Figure 3

Visualization of the gene-sets and pathways enriched in primary GSEA analysis (A) and replicated in VEGAS and PASCAL (B). The size of the nodes corresponds to the number of the genes associated with a term. The significance is represented by the color of the nodes (P < 0.05, 0.05 < P < 0.1 and P > 0.1 are represented by red, yellow and gray, respectively).