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GWAS 和 eQTL 研究汇总数据的综合分析提示了在阿尔茨海默病中差异表达的基因。

Integrative analysis of summary data from GWAS and eQTL studies implicates genes differentially expressed in Alzheimer's disease.

机构信息

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.

出版信息

BMC Genomics. 2022 Jun 2;23(Suppl 4):414. doi: 10.1186/s12864-022-08584-8.

DOI:10.1186/s12864-022-08584-8
PMID:35655140
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9161451/
Abstract

BACKGROUND

Although genome-wide association studies (GWAS) have successfully located various genetic variants susceptible to Alzheimer's Disease (AD), it is still unclear how specific variants interact with genes and tissues to elucidate pathologies associated with AD. Summary-data-based Mendelian Randomization (SMR) addresses this problem through an instrumental variable approach that integrates data from independent GWAS and expression quantitative trait locus (eQTL) studies in order to infer a causal effect of gene expression on a trait.

RESULTS

Our study employed the SMR approach to integrate a set of meta-analytic cis-eQTL information from the Genotype-Tissue Expression (GTEx), CommonMind Consortium (CMC), and Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) consortiums with three sets of meta-analysis AD GWAS results.

CONCLUSIONS

Our analysis identified twelve total gene probes (associated with twelve distinct genes) with a significant association with AD. Four of these genes survived a test of pleiotropy from linkage (the HEIDI test).Three of these genes - RP11-385F7.1, PRSS36, and AC012146.7 - have not yet been reported differentially expressed in the brain in the context of AD, and thus are the novel findings warranting further investigation.

摘要

背景

尽管全基因组关联研究 (GWAS) 已成功定位到各种易患阿尔茨海默病 (AD) 的遗传变异，但仍不清楚特定变异如何与基因和组织相互作用，以阐明与 AD 相关的病理。基于汇总数据的孟德尔随机化 (SMR) 通过一种工具变量方法解决了这个问题，该方法整合了来自独立的 GWAS 和表达数量性状基因座 (eQTL) 研究的数据，以推断基因表达对性状的因果影响。

结果

我们的研究采用 SMR 方法，将来自 Genotype-Tissue Expression (GTEx)、CommonMind 联盟 (CMC)、宗教秩序研究和拉什记忆与衰老项目 (ROS/MAP) 联盟的一组荟萃分析顺式-eQTL 信息与三项荟萃分析 AD GWAS 结果相结合。

结论

我们的分析确定了与 AD 显著相关的总共十二个基因探针（与十二个不同的基因相关）。其中四个基因通过连锁的同位性检验（HEIDI 检验）幸存下来。这四个基因中的三个 - RP11-385F7.1、PRSS36 和 AC012146.7 - 在 AD 背景下在大脑中尚未报道过差异表达，因此是值得进一步研究的新发现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/421318827b00/12864_2022_8584_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/157ede020170/12864_2022_8584_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/82a2553c282c/12864_2022_8584_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/1c9c4eaae550/12864_2022_8584_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/7b54a74f7224/12864_2022_8584_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/90a296525176/12864_2022_8584_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/9f60d30a492a/12864_2022_8584_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/421318827b00/12864_2022_8584_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/157ede020170/12864_2022_8584_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/b0d6aec58194/12864_2022_8584_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/82a2553c282c/12864_2022_8584_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/1c9c4eaae550/12864_2022_8584_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/7b54a74f7224/12864_2022_8584_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/90a296525176/12864_2022_8584_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/9f60d30a492a/12864_2022_8584_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dcf/9161451/421318827b00/12864_2022_8584_Fig8_HTML.jpg

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