Delineating the Genetic Component of Gene Expression in Major Depression.
Delineating the Genetic Component of Gene Expression in Major Depression.
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DOI：
10.1016/j.biopsych.2020.09.010
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发表时间：
2021-03-15
影响因子：
10.6
通讯作者：
Pain O
中科院分区：
文献类型：
--
作者：
Dall'Aglio L;Lewis CM;Pain O
重度抑郁症（MD）是由多种因素决定的，包括调节基因表达的遗传风险变异。我们通过全转录组关联研究（TWAS），从遗传、转录组和表型信息推断基因表达与性状的关系，研究了MD基因表达的遗传成分。抑郁症中差异表达的基因是用TWAS FUSION方法鉴定的，基于来自MD最大全基因组关联分析的汇总统计（n = 135，458例，n = 344，901对照）和来自21个组织数据集（脑;血液;甲状腺，肾上腺和垂体）的基因表达水平。进行了随访分析，以广泛表征所确定的相关性：共定位，条件和精细映射分析以及基于TWAS的途径研究。病例组和对照组之间在94个基因上存在显著差异，其中大约一半是新的。在94个重要基因中，有6个基因与抑郁症有很强的、共定位的、潜在的因果关系。这种高置信度关联包括NEGR 1、CTC-467M3.3、TMEM 106 B、LRFN 5、ESR 2和PROX 2。最后，基于TWAS的富集分析突出了神经元和突触过程等基因组的失调。这项研究揭示了进一步阐明抑郁症的基因表达的遗传组成部分，通过表征所确定的协会，解开新的风险基因，并确定哪些协会是一致的因果模型。这些研究结果可以作为一个资源，优先考虑和设计后续的功能研究的MD。
Major depression (MD) is determined by a multitude of factors including genetic risk variants that regulate gene expression. We examined the genetic component of gene expression in MD by performing a transcriptome-wide association study (TWAS), inferring gene expression–trait relationships from genetic, transcriptomic, and phenotypic information. Genes differentially expressed in depression were identified with the TWAS FUSION method, based on summary statistics from the largest genome-wide association analysis of MD (n = 135,458 cases, n = 344,901 controls) and gene expression levels from 21 tissue datasets (brain; blood; thyroid, adrenal, and pituitary glands). Follow-up analyses were performed to extensively characterize the identified associations: colocalization, conditional, and fine-mapping analyses together with TWAS-based pathway investigations. Transcriptome-wide significant differences between cases and controls were found at 94 genes, approximately half of which were novel. Of the 94 significant genes, 6 represented strong, colocalized, and potentially causal associations with depression. Such high-confidence associations include NEGR1, CTC-467M3.3, TMEM106B, LRFN5, ESR2, and PROX2. Lastly, TWAS-based enrichment analysis highlighted dysregulation of gene sets for, among others, neuronal and synaptic processes. This study sheds further light on the genetic component of gene expression in depression by characterizing the identified associations, unraveling novel risk genes, and determining which associations are congruent with a causal model. These findings can be used as a resource for prioritizing and designing subsequent functional studies of MD.
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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
影响因子：
3.7
作者：
Lopez-Duran, Nestor L.;Kovacs, Maria;George, Charles J.
通讯作者：
George, Charles J.
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
14.9
作者：
Geer LY;Marchler-Bauer A;Geer RC;Han L;He J;He S;Liu C;Shi W;Bryant SH
通讯作者：
Bryant SH
影响因子：
11
作者：
Milaneschi, Yuri;Simmons, W Kyle;Penninx, Brenda Wjh
通讯作者：
Penninx, Brenda Wjh