title: Somatic signature of brain-specific single nucleotide variations in sporadic Alzheimer's disease.
abstract: BACKGROUND
  Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown.
  
  
  OBJECTIVE
  The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples.
  
  
  METHODS
  By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients.
  
  
  RESULTS
  We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients.
  
  
  CONCLUSIONS
  Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Parcerisas
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Rubio
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Muhaisen
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gómez-Ramos
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Pujadas
authors.affiliation: Joint IRB-BSC Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Puiggros
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ureña
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Ferrán
authors.initials: F
authors.lastname: Burgaya
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Torrents
authors.affiliation: Fundación CIEN, Vallecas, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Spain Fundación CIEN, Vallecas, Madrid, Spain Vall d'Hebrón Institut de Recerca (VHIR), Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D015140:Dementia, Vascular / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
keywords: Alzheimer's disease; exome sequencing; somatic variations