title: Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.
abstract: BACKGROUND
  We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.
  
  
  METHODS
  We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.
  
  
  RESULTS
  We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.
  
  
  CONCLUSIONS
  Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA. Electronic address: smukherj@uw.edu.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Russell
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Carr
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Burgess
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Serie
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, USA; Department of Neuroscience, Brigham Young University, Provo, Utah, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Boehme
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, USA; Department of Neuroscience, Brigham Young University, Provo, Utah, USA.
authors.forename: John S K
authors.initials: JSK
authors.lastname: Kauwe
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Naj
authors.affiliation: Department of Biostatistics, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Matt R
authors.initials: MR
authors.lastname: Kaeberlein
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055106:Genome-Wide Association Study; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D060066:Protein Interaction Maps; D034622:RNA Interference / Q000502:physiology; D049490:Systems Biology; D013702:Temporal Lobe / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000951:Antigens, Neoplasm; D051766:Early Growth Response Protein 1; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D026901:Membrane Transport Proteins; C440529:UBC antigen; C021723:oxoglutarate translocator; D000226:Mitochondrial ADP, ATP Translocases; D009245:NADH Dehydrogenase; C000594261:ATP5PD protein, human; C472512:NDUFS3 protein, human
keywords: Alzheimer's disease; Brain expression; C. elegans; Network analysis; Protein-protein interaction; SNP; Systems biology