TY - JOUR
T1 - Late-onset Alzheimer disease risk variants mark brain regulatory loci
AU - Allen, Mariet
AU - Kachadoorian, Michaela
AU - Carrasquillo, Minerva M.
AU - Karhade, Aditya
AU - Manly, Lester
AU - Burgess, Jeremy D.
AU - Wang, Chen
AU - Serie, Daniel
AU - Wang, Xue
AU - Siuda, Joanna
AU - Zou, Fanggeng
AU - Chai, High Seng
AU - Younkin, Curtis
AU - Crook, Julia
AU - Medway, Christopher
AU - Nguyen, Thuy
AU - Ma, Li
AU - Malphrus, Kimberly
AU - Lincoln, Sarah
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Asmann, Yan W.
AU - Dickson, Dennis W.
AU - Younkin, Steven G.
AU - Ertekin-Taner, Nilüfer
N1 - Publisher Copyright:
©2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
PY - 2015/8
Y1 - 2015/8
N2 - Objective: To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation. Methods: Expression levels from the cerebellum(CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WGDASL) for∼400 autopsied patients (∼200 with AD and ∼200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within ±100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis-SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq). Results: We identified strong associations of brain CR1, HLA-DRB1, and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis-SNPs for LOAD candidate genes MEF2C, ZCWPW1, and SLC24A4. MEF2C and SLC24A4, but not ZCWPW1 cis-SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1, HLA-DRB1, ZCWPW1, and SLC24A4. Conclusions: Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.
AB - Objective: To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation. Methods: Expression levels from the cerebellum(CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WGDASL) for∼400 autopsied patients (∼200 with AD and ∼200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within ±100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis-SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq). Results: We identified strong associations of brain CR1, HLA-DRB1, and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis-SNPs for LOAD candidate genes MEF2C, ZCWPW1, and SLC24A4. MEF2C and SLC24A4, but not ZCWPW1 cis-SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1, HLA-DRB1, ZCWPW1, and SLC24A4. Conclusions: Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.
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U2 - 10.1212/NXG.0000000000000012
DO - 10.1212/NXG.0000000000000012
M3 - Article
AN - SCOPUS:84969943555
SN - 2376-7839
VL - 1
JO - Neurology: Genetics
JF - Neurology: Genetics
IS - 2
M1 - e15
ER -