晚发性阿尔茨海默病风险变异标记大脑调控基因座。
Late-onset Alzheimer disease risk variants mark brain regulatory loci.
机构信息
Department of Neuroscience (M.A., M.K., M.M.C., A.K., L. Manly, J.D.B., J.S., F.Z., C.Y., C.M., T.N., L. Ma, K.M., S.L., D.W.D., S.G.Y., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), and Health Sciences Research (D.S., X.W., J.C., Y.W.A.), Mayo Clinic, Jacksonville, FL; Department of Neurology (R.C.P.) and Health Sciences Research (C.W., H.S.C.), Mayo Clinic, Rochester, MN; and Department of Neurology (J.S.), Medical University of Silesia, Katowice, Poland.
出版信息
Neurol Genet. 2015 Jul 23;1(2):e15. doi: 10.1212/NXG.0000000000000012. eCollection 2015 Aug.
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 (WG-DASL) 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.
目的
通过基因表达调控，调查国际阿尔茨海默病基因组计划（IGAP）发现或证实的与大脑基因表达水平相关的阿尔茨海默病（AD）的最高晚期发病风险（LOAD）基因座，以鉴定通过基因表达调节影响 AD 风险的变体。
方法
使用 Illumina 全基因组 cDNA 介导的退火、选择、延伸和连接测定法（WG-DASL），从 400 例尸检患者（约 200 例 AD 和 200 例非 AD 病理学患者）的小脑（CER）和颞叶皮层（TCX）中获得表达水平。我们测试了 12 个显著的 LOAD 全基因组关联研究（GWAS）指数单核苷酸多态性（SNP）与 ±100kb 内的 34 个基因的水平的顺式关联。我们还评估了 LOAD GWAS 候选基因的 14 个大脑水平与 1899 个顺式-SNP 的关联。使用下一代 RNA 测序（RNAseq）在 TCX 样本的子集中验证了显著的关联。
结果
我们确定了大脑 CR1、HLA-DRB1 和 PILRB 水平与 LOAD GWAS 指数 SNP 的强烈关联。我们还检测到其他 LOAD 候选基因 MEF2C、ZCWPW1 和 SLC24A4 的强顺式-SNP。MEF2C 和 SLC24A4，但不是 ZCWPW1 顺式-SNP，也与 LOAD 风险相关，独立于指数 SNP。TCX 表达关联可以通过 RNAseq 验证 CR1、HLA-DRB1、ZCWPW1 和 SLC24A4。
结论
我们的结果表明，一些 LOAD GWAS 变体标记了大脑调节基因座，提名了受 LOAD 风险变体调节的基因，并为这些变体的大脑调节作用进行了注释。
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