PT  - JOURNAL ARTICLE
AU  - Galen E.B. Wright
AU  - Nicholas S. Caron
AU  - Bernard Ng
AU  - Lorenzo Casal
AU  - Xiaohong Xu
AU  - Jolene Ooi
AU  - Mahmoud A. Pouladi
AU  - Sara Mostafavi
AU  - Colin J.D. Ross
AU  - Michael R. Hayden
TI  - Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease
AID  - 10.1101/699033
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 699033
4099  - http://biorxiv.org/content/early/2019/07/11/699033.short
4100  - http://biorxiv.org/content/early/2019/07/11/699033.full
AB  - Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in the HTT gene. In an attempt to identify genomic modifiers that contribute towards the age of onset of HD, we performed a transcriptome wide association study assessing heritable differences in genetically determined expression in diverse tissues, employing genome wide data from over 4,000 patients. This identified genes that showed evidence for colocalization and replication, with downstream functional validation being performed in isogenic HD stem cells and patient brains. Enrichment analyses detected associations with various biologically-relevant gene sets and striatal coexpression modules that are mediated by CAG length. Further, cortical coexpression modules that are relevant for HD onset were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder.