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Am J Hum Genet DOI:10.1016/j.ajhg.2012.02.022

Alzheimer disease susceptibility loci: evidence for a protein network under natural selection.

Publication TypeJournal Article
Year of Publication2012
AuthorsRaj, T, Shulman, JM, Keenan, BT, Chibnik, LB, Evans, DA, Bennett, DA, Stranger, BE, De Jager, PL
JournalAm J Hum Genet
Date Published2012 Apr 06
KeywordsAdaptor Proteins, Signal Transducing, Age of Onset, Alzheimer Disease, Cytoskeletal Proteins, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Monomeric Clathrin Assembly Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Protein Interaction Maps, Receptor, EphA1, Selection, Genetic, Tumor Suppressor Proteins

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID22482808
PubMed Central IDPMC3322230
Grant ListK08 AG034290 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
R01 AG11101 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
R01 AG30146 / AG / NIA NIH HHS / United States
R01 AG011101 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
R01 AG179917 / AG / NIA NIH HHS / United States