Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation.
Highlights
Huntington’s disease (HD) is a neurodegenerative disorder with classic symptoms that include progressive chorea, motor deWcits, cognitive changes and dementia
We genotyped a collection of 1,929 HD DNA samples, with known HD CAG allele sizes and known age at onset of motor symptoms, for the PPARGC1A rs7665116 polymorphism
In two of the previous reports, the association with at onset (AO) was primarily observed in HD patients of Italian ancestry (Che et al 2011; Weydt et al 2009); we split our large cohort by ancestry into either Southern European or Western European HD cases
Summary
Huntington’s disease (HD) is a neurodegenerative disorder with classic symptoms that include progressive chorea, motor deWcits, cognitive changes and dementia. Age at onset (AO) of the overt symptoms is highly variable: while some individuals show signs in the Wrst decade, others remain asymptomatic even after 60 years of age, though in most cases death follows on average about 17 years after the Wrst symptoms. HD is inherited as an autosomal dominant trait and is caused by the expansion of an unstable CAG repeat, in the Wrst exon of the HD gene ( called HTT), on chromosome 4p16.3 (The Huntington’s Disease Collaborative Research Group 1993), resulting in an expanded polyglutamine tract in the huntingtin protein. Many of the speciWc polymorphisms assessed in multiple studies have failed to be replicated, including attractive biological candidate genes such as glutamate receptor, ionotropic kainate 2 (GRIK2), apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) (Rubinsztein et al 1997; Metzger et al 2006; Panas et al 1999; Alberch et al 2005; Di Maria et al 2006)
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