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

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.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2012; 90(4):720-6. DOI: 10.1016/j.ajhg.2012.02.022
Source: PubMed


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.

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    • "the gene coding region but not in the coding region , have been identified to influence AD risk ( Harold et al . , 2009 ; Lambert et al . , 2009 ; Carrasquillo et al . , 2010 , 2015 ; Chen et al . , 2012 ; Tanzi , 2012 ; Liu et al . , 2013 ; Morgen et al . , 2014 ) . It has been reported that some AD - associated SNPs influence PICALM expression ( Raj et al . , 2012 ) . We recently studied the highly validated rs3851179 PICALM variants whose rs3851179 A allele is associated with a lower AD risk than the rs3851179 G allele ( Lambert et al . , 2009 , 2013 ) using inducible pluripotent stem cell ( iPSC ) - derived endothelial cells . These studies revealed that the protective rs3851179 A allele signif"
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