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

Towfique Raj, Joshua M. Shulman, Brendan T. Keenan, Lori B. Chibnik, Denis A. Evans, David A. Bennett, Barbara E. Stranger, Philip L. De Jager

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish
Pages (from-to)720-726
Number of pages7
JournalAmerican Journal of Human Genetics
Volume90
Issue number4
DOIs
StatePublished - 6 Apr 2012
Externally publishedYes

Fingerprint

Dive into the research topics of 'Alzheimer disease susceptibility loci: Evidence for a protein network under natural selection'. Together they form a unique fingerprint.

Cite this