title: Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease.
abstract: Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.
authors.affiliation: Department of Pathology, Columbia University, 650 W. 168th Street, New York, New York 10032, USA.
authors.forename: Herve
authors.initials: H
authors.lastname: Rhinn
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Fujita
authors.forename: Liang
authors.initials: L
authors.lastname: Qiang
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Asa
authors.initials: A
authors.lastname: Abeliovich
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D004705:Endocytosis; D004843:Epistasis, Genetic; D005260:Female; D005347:Fibroblasts; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics; D006579:Heterozygote; D006801:Humans; D000077287:Levetiracetam; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C076414:SV2A protein, human; D000077287:Levetiracetam; D010889:Piracetam