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

Eliana Marisa Ramos, Jeanne C. Latourelle, Ji Hyun Lee, Tammy Gillis, Jayalakshmi S. Mysore, Ferdinando Squitieri, Alba Di Pardo, Stefano Di Donato, Michael R. Hayden, Patrick J. Morrison, Martha Nance, Christopher A. Ross, Russell L. Margolis, Estrella Gomez-Tortosa, Carmen Ayuso, Oksana Suchowersky, Ronald J. Trent, Elizabeth McCusker, Andrea Novelletto, Marina FrontaliRandi Jones, Tetsuo Ashizawa, Samuel Frank, Marie Helene Saint-Hilaire, Steven M. Hersch, Herminia D. Rosas, Diane Lucente, Madaline B. Harrison, Andrea Zanko, Karen Marder, James F. Gusella, Jong Min Lee, Isabel Alonso, Jorge Sequeiros, Richard H. Myers, Marcy E. MacDonald

Research output: Contribution to journalArticle

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 modiWer of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these Wndings 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 stratiWcation. 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 modiWer of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratiWcation among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reXect population diVerences in genetic or environmental factors that warrant further investigation.

Original languageEnglish (US)
Pages (from-to)1833-1840
Number of pages8
JournalHuman genetics
Volume131
Issue number12
DOIs
StatePublished - Dec 1 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Ramos, E. M., Latourelle, J. C., Lee, J. H., Gillis, T., Mysore, J. S., Squitieri, F., Di Pardo, A., Di Donato, S., Hayden, M. R., Morrison, P. J., Nance, M., Ross, C. A., Margolis, R. L., Gomez-Tortosa, E., Ayuso, C., Suchowersky, O., Trent, R. J., McCusker, E., Novelletto, A., ... MacDonald, M. E. (2012). Population stratiWcation may bias analysis of PGC-1α as a modiWer of age at Huntington disease motor onset. Human genetics, 131(12), 1833-1840. https://doi.org/10.1007/s00439-012-1205-z