TY - JOUR
T1 - Alzheimer disease susceptibility loci
T2 - Evidence for a protein network under natural selection
AU - Raj, Towfique
AU - Shulman, Joshua M.
AU - Keenan, Brendan T.
AU - Chibnik, Lori B.
AU - Evans, Denis A.
AU - Bennett, David A.
AU - Stranger, Barbara E.
AU - De Jager, Philip L.
N1 - Funding Information:
This work is supported by the National Institutes of Health (NIH) (RC2 GM093080, R01 AG30146, R01 AG179917, R01 AG15819, K08 AG034290, P30 AG10161 and R01 AG11101). J.M.S. was additionally supported by the Burroughs Wellcome Fund. We thank the Brigham and Women's Hospital PhenoGenetic Project for providing mRNA samples from healthy subjects that were used in the CD4+ T lymphocyte transcriptional analysis for this study. We thank Michelle Lee for sample collection, Katherine Rothamel for data generation, and Scott Davis for mRNA expression quality control. We thank Christophe Benoist for his leadership on RC2 GM093080. These analyses were conducted under the auspices of a protocol approved by the institutional review board of Partners Healthcare.
PY - 2012/4/6
Y1 - 2012/4/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859499759&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.02.022
DO - 10.1016/j.ajhg.2012.02.022
M3 - Article
C2 - 22482808
AN - SCOPUS:84859499759
SN - 0002-9297
VL - 90
SP - 720
EP - 726
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -