Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue.
Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue.
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血液和脑组织中与阿尔茨海默病相关的细胞类型特异性表达数量性状位点
DOI：
10.1038/s41398-021-01373-z
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发表时间：
2021-04-27
影响因子：
6.8
通讯作者：
Farrer LA
中科院分区：
文献类型：
--
作者：
Patel D;Zhang X;Farrell JJ;Chung J;Stein TD;Lunetta KL;Farrer LA
由于基因表达的调节是可遗传的且依赖于环境，因此我们研究了血液和大脑细胞类型中与 AD 相关的基因表达模式。对 5257 名弗雷明汉心脏研究 (FHS) 参与者的血液和 475 名宗教秩序研究/记忆与衰老项目 (ROSMAP) 参与者捐赠的大脑进行了全基因组顺式表达数量性状基因座 (eQTL) 作图。使用不相关受试者的线性回归模型和相关受试者的线性混合模型来评估基因表达与1 Mb基因内的所有顺式SNP的基因型的关联。细胞类型特异性 eQTL (ct-eQTL) 模型包括用于区分特定细胞类型的“代理”基因表达的相互作用术语。 Ct-eQTL 分析分别在大脑和血液中识别出 11,649 和 2533 个额外的显着基因 SNP eQTL 对，这些基因-SNP eQTL 对在通用 eQTL 分析中未检测到。值得注意的是，血液和大脑之间共享的重要 eQTL 的 386 个独特目标 eGene 在细胞凋亡和 Wnt 信号通路中富集。其中五个共享基因已建立 AD 基因座。骨髓细胞类型中的显着结果对 AD 的潜在重要性和相关性得到了以下观察结果的支持：大部分 GWS ct-eQTL 位于已建立的 AD 位点的 1 Mb 范围内，并且这些 eQTL 中 58% (23/40) 的最重要的 eGene 先前已与 AD 相关。这项研究确定了已建立的和潜在的新型 AD 基因的细胞类型特异性表达模式，发现了骨髓细胞在 AD 风险中的作用的更多证据，并发现了潜在的新型血液和大脑 AD 生物标志物，这些生物标志物强调了细胞类型特异性分析的重要性。
Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of “proxy” genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.
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影响因子：
3.3
作者：
Hallock, Peter;Thomas, Michael A.
通讯作者：
Thomas, Michael A.
影响因子：
3.7
作者：
de Kreuk BJ;Schaefer A;Anthony EC;Tol S;Fernandez-Borja M;Geerts D;Pool J;Hambach L;Goulmy E;Hordijk PL
通讯作者：
Hordijk PL
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
DOI：
10.3233/jad-150088
发表时间：
2015
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Dinkins MB;Dasgupta S;Wang G;Zhu G;He Q;Kong JN;Bieberich E
通讯作者：
Bieberich E
影响因子：
16.6
作者：
Donovan, Margaret K. R.;D'Antonio-Chronowska, Agnieszka;Frazer, Kelly A.
通讯作者：
Frazer, Kelly A.