Huntington's disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer's disease.
There is widespread transcriptional dysregulation in Huntington's disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer's disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches.
Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1B 5EH, UK.
Davina J
DJ
Hensman Moss
Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1B 5EH, UK.
Michael D
MD
Flower
University College London Genetics Institute, University College London, London, WC1E 6BT, UK.
Kitty K
KK
Lo
Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1B 5EH, UK.
James R C
JR
Miller
Department of Human Genetics, Leiden University Medical Center, Leiden, Postzone S-4-P, The Netherlands.
Gert-Jan B
GB
van Ommen
Department of Human Genetics, Leiden University Medical Center, Leiden, Postzone S-4-P, The Netherlands.
Peter A C
PA
't Hoen
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, CF24 4HQ, UK.
Timothy C
TC
Stone
Faculty of Education, University of Cambridge, CB2 8PQ, Cambridge UK.
Amelia
A
Guinee
Departments of Psychiatry and Biostatistics, University of Iowa, IA 52242, USA.
Douglas R
DR
Langbehn
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, CF24 4HQ, UK.
Lesley
L
Jones
University College London Genetics Institute, University College London, London, WC1E 6BT, UK.
Vincent
V
Plagnol
Department of Human Genetics, Leiden University Medical Center, Leiden, Postzone S-4-P, The Netherlands.
Willeke M C
WM
van Roon-Mom
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, CF24 4HQ, UK.
Peter
P
Holmans
Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1B 5EH, UK.
Sarah J
SJ
Tabrizi
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D015415:Biomarkers; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D007109:Immunity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D055815:Young Adult
D015415:Biomarkers