TY - JOUR
T1 - Population stratiWcation may bias analysis of PGC-1α as a modiWer of age at Huntington disease motor onset
AU - Ramos, Eliana Marisa
AU - Latourelle, Jeanne C.
AU - Lee, Ji Hyun
AU - Gillis, Tammy
AU - Mysore, Jayalakshmi S.
AU - Squitieri, Ferdinando
AU - Di Pardo, Alba
AU - Di Donato, Stefano
AU - Hayden, Michael R.
AU - Morrison, Patrick J.
AU - Nance, Martha
AU - Ross, Christopher A.
AU - Margolis, Russell L.
AU - Gomez-Tortosa, Estrella
AU - Ayuso, Carmen
AU - Suchowersky, Oksana
AU - Trent, Ronald J.
AU - McCusker, Elizabeth
AU - Novelletto, Andrea
AU - Frontali, Marina
AU - Jones, Randi
AU - Ashizawa, Tetsuo
AU - Frank, Samuel
AU - Saint-Hilaire, Marie Helene
AU - Hersch, Steven M.
AU - Rosas, Herminia D.
AU - Lucente, Diane
AU - Harrison, Madaline B.
AU - Zanko, Andrea
AU - Marder, Karen
AU - Gusella, James F.
AU - Lee, Jong Min
AU - Alonso, Isabel
AU - Sequeiros, Jorge
AU - Myers, Richard H.
AU - MacDonald, Marcy E.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-012-1205-z
DO - 10.1007/s00439-012-1205-z
M3 - Article
C2 - 22825315
AN - SCOPUS:84870996209
VL - 131
SP - 1833
EP - 1840
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 12
ER -