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

Hum Genet. 2012 Dec;131(12):1833-40. doi: 10.1007/s00439-012-1205-z. Epub 2012 Jul 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Cohort Studies
  • Europe / epidemiology
  • Female
  • Genetics, Population
  • Heat-Shock Proteins / genetics*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / epidemiology
  • Huntington Disease / genetics*
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Polymorphism, Single Nucleotide*
  • Transcription Factors / genetics*
  • Trinucleotide Repeat Expansion

Substances

  • HTT protein, human
  • Heat-Shock Proteins
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors