title: Common disease signatures from gene expression analysis in Huntington's disease human blood and brain.
abstract: Huntington's disease (HD) is a devastating brain disorder with no effective treatment or cure available. The scarcity of brain tissue makes it hard to study changes in the brain and impossible to perform longitudinal studies. However, peripheral pathology in HD suggests that it is possible to study the disease using peripheral tissue as a monitoring tool for disease progression and/or efficacy of novel therapies. In this study, we investigated if blood can be used to monitor disease severity and progression in brain. Since previous attempts using only gene expression proved unsuccessful, we compared blood and brain Huntington's disease signatures in a functional context.
  
  
  
  Microarray HD gene expression profiles from three brain regions were compared to the transcriptome of HD blood generated by next generation sequencing. The comparison was performed with a combination of weighted gene co-expression network analysis and literature based functional analysis (Concept Profile Analysis). Uniquely, our comparison of blood and brain datasets was not based on (the very limited) gene overlap but on the similarity between the gene annotations in four different semantic categories: "biological process", "cellular component", "molecular function" and "disease or syndrome".
  
  
  
  We identified signatures in HD blood reflecting a broad pathophysiological spectrum, including alterations in the immune response, sphingolipid biosynthetic processes, lipid transport, cell signaling, protein modification, spliceosome, RNA splicing, vesicle transport, cell signaling and synaptic transmission. Part of this spectrum was reminiscent of the brain pathology. The HD signatures in caudate nucleus and BA4 exhibited the highest similarity with blood, irrespective of the category of semantic annotations used. BA9 exhibited an intermediate similarity, while cerebellum had the least similarity. We present two signatures that were shared between blood and brain: immune response and spinocerebellar ataxias.
  
  
  
  Our results demonstrate that HD blood exhibits dysregulation that is similar to brain at a functional level, but not necessarily at the level of individual genes. We report two common signatures that can be used to monitor the pathology in brain of HD patients in a non-invasive manner. Our results are an exemplar of how signals in blood data can be used to represent brain disorders. Our methodology can be used to study disease specific signatures in diseases where heterogeneous tissues are involved in the pathology.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. e.mina@lumc.nl.
authors.forename: Eleni
authors.identifier: 0000-0002-8972-9206
authors.initials: E
authors.lastname: Mina
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Willeke
authors.initials: W
authors.lastname: van Roon-Mom
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Kristina
authors.initials: K
authors.lastname: Hettne
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: van Zwet
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Goeman
authors.affiliation: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Institute of Biology Paris-Seine, 9 quai Saint Bernard, Paris, 75005, France.|Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, 4 place Jussieu, Paris, 75005, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Neri
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: A C 't Hoen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Barend
authors.initials: B
authors.lastname: Mons
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Roos
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006816:Huntington Disease / Q000097:blood* / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers
keywords: Biomarker discovery; Blood; Concept profile analysis; Huntington’s disease; WGCNA