Background A polyglutamine repeat expansion of more than 36 units in the huntingtin protein is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age at onset (AAO) but additional genetic factors apart from the expanded CAG repeat length can modify the course and AAO in HD. Until now, among others the gene encoding PCG-1α, a transcriptional coactivator in metabolic processes that seems to be defective in HD, could be identified to modify the AAO in two independent populations.

Aim/method As the identification of distinct modifiers in association studies is generally dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNP) in the PGC-1α gene for a disease modifying effect in more than 800 European HD patients.

Results Two SNPs, one in the promotor and one in the transcribed region of the PGC-1α gene, showed a significant effect on the AAO. While the variant allele of SNP rs7665116 was associated with a delay in disease onset, the variant allele of SNP rs2970870 leads to an earlier onset of HD in its homozygous state.

Conclusion Therefore, our results indicate opposing modifying influences of one gene to disease pathology and support the concept of a reduced PGC-1α expression due to mutant huntingtin as well as an altered functionality of PGC-1α towards target genes in HD pathogenesis.