Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset.

Center for Human Genetic Research, Massachusetts General Hospital, Simches Research Building, Room 5414, 185 Cambridge Street, Boston, MA, 02114, USA.
Human Genetics (Impact Factor: 4.63). 07/2012; DOI: 10.1007/s00439-012-1205-z
Source: PubMed

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.

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    ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3' UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
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    ABSTRACT: Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the HTT gene. Although the variation in age at onset (AO) is partly explained by the length of the expanded repeat blocks, the unexplained variation in AO is highly heritable, emphasizing the role of modifier genes on disease expression. Since down-regulation of type 1 cannabinoid (CB1) receptors is a key pathogenic event in HD, it has been suggested that activation of these receptors in patients may attenuate disease progression. In order to evaluate whether variations in the cannabinoid receptor 1 (CNR1) gene encoding the CB1 receptor protein have modifying effects on the AO of HD, we performed an association study between CNR1 polymorphisms and AO in HD patients. A (AAT)n repeat and a total of nine single nucleotide polymorphisms (SNPs) in the CNR1 gene were selected for genotyping in a cohort of 473 German HD patients recruited in the Huntington Center NRW in Bochum. The AO was significantly associated with the longest alleles (≥ 17 AAT) of the (AAT)n repeat polymorphism downstream of the CNR1 gene (p = 0.007) as well as with one SNP in the 3'UTR of CNR1 (rs4707436, p = 0.05). Interestingly, the allelic variation of rs4707436 affects different microRNA (miRNA) binding sites which could alter gene regulation and consequently influence protein expression. These findings support the idea that CNR1 variation may have modifying effects on the AO in HD.
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