Alzheimer Disease Susceptibility Loci: Evidence for a Protein Network under Natural Selection

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 na...

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Bibliographic Details
Published in:American journal of human genetics 2012-04, Vol.90 (4), p.720-726
Main Authors: Raj, Towfique, Shulman, Joshua M., Keenan, Brendan T., Chibnik, Lori B., Evans, Denis A., Bennett, David A., Stranger, Barbara E., De Jager, Philip L.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Age of Onset
Alzheimer Disease - genetics
Alzheimer's disease
Biological and medical sciences
Coevolution
Cytoskeletal Proteins - genetics
Data processing
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Fundamental and applied biological sciences. Psychology
Gene loci
General aspects. Genetic counseling
Genetic Loci
Genetic Predisposition to Disease
Genetics
Genetics of eukaryotes. Biological and molecular evolution
Genome-Wide Association Study
Genomes
Genomics
Haplotypes
Humans
Medical genetics
Medical sciences
Molecular and cellular biology
Monomeric Clathrin Assembly Proteins - genetics
Movement disorders
Natural selection
Neurodegenerative diseases
Neurology
Nuclear Proteins - genetics
Parkinson's disease
Polymorphism, Single Nucleotide
Positive selection
Protein interaction
Protein Interaction Maps - genetics
Proteins
Receptor, EphA1 - genetics
Selection, Genetic
Tumor Suppressor Proteins - genetics
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2012.02.022