title: Alzheimer disease susceptibility loci: evidence for a protein network under natural selection.
abstract: Recent genome-wide association studies have identified a number of susceptibility loci for Alzheimer disease (AD). To understand the functional consequences and potential interactions of the associated loci, we explored large-scale data sets interrogating the human genome for evidence of positive natural selection. Our findings provide significant evidence for signatures of recent positive selection acting on several haplotypes carrying AD susceptibility alleles; interestingly, the genes found in these selected haplotypes can be assembled, independently, into a molecular complex via a protein-protein interaction (PPI) network approach. These results suggest a possible coevolution of genes encoding physically-interacting proteins that underlie AD susceptibility and are coexpressed in different tissues. In particular, PICALM, BIN1, CD2AP, and EPHA1 are interconnected through multiple interacting proteins and appear to have coordinated evidence of selection in the same human population, suggesting that they may be involved in the execution of a shared molecular function. This observation may be AD-specific, as the 12 loci associated with Parkinson disease do not demonstrate excess evidence of natural selection. The context for selection is probably unrelated to AD itself; it is likely that these genes interact in another context, such as in immune cells, where we observe cis-regulatory effects at several of the selected AD loci.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Denis A
authors.initials: DA
authors.lastname: Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics; D036082:Receptor, EphA1 / Q000235:genetics; D012641:Selection, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D034041:Monomeric Clathrin Assembly Proteins; D009687:Nuclear Proteins; C439003:PICALM protein, human; D025521:Tumor Suppressor Proteins; D036082:Receptor, EphA1