Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features.
Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features.
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精神分裂症遗传危险因素和转录组特征之间的关联有限。
DOI：
10.3390/genes12071062
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发表时间：
2021-07-12
期刊：
影响因子：
3.5
通讯作者：
Won H
中科院分区：
文献类型：
--
作者：
Yu AW;Peery JD;Won H
精神分裂症是一种多基因疾病，许多基因组区域与精神分裂症风险有关。大多数与精神分裂症相关的遗传变异存在于非编码基因组中，并被认为有助于转录调节。从精神分裂症患者的死后脑样本中检测到广泛的转录组失调。然而，精神分裂症遗传危险因素与转录组学特征之间的关系尚待探讨。在此，我们研究了不同的基因表达特征，包括差异表达基因（DEGs）、共表达网络和基因的中心枢纽性，是否有助于精神分裂症的遗传性。我们利用数量性状位点和染色质相互作用谱来确定分配给代表不同转录组特征的基因的精神分裂症风险变异。然后，我们对这些变异进行分层连锁不平衡评分回归分析，以估计不同基因表达特征的精神分裂症遗传力富集。值得注意的是，基因变异基因和共表达网络表现出名义上的遗传力富集。这种名义上的关联可以部分解释为细胞异质性，因为deg以细胞类型特异性的方式与精神分裂症的遗传风险相关。此外，精神分裂症相关转录因子靶基因的DEGs富集，表明精神分裂症的转录组特征是遗传危险因素引发的转录调控级联反应的结果。
Schizophrenia is a polygenic disorder with many genomic regions contributing to schizophrenia risk. The majority of genetic variants associated with schizophrenia lie in the non-coding genome and are thought to contribute to transcriptional regulation. Extensive transcriptomic dysregulation has been detected from postmortem brain samples of schizophrenia-affected individuals. However, the relationship between schizophrenia genetic risk factors and transcriptomic features has yet to be explored. Herein, we examined whether varying gene expression features, including differentially expressed genes (DEGs), co-expression networks, and central hubness of genes, contribute to the heritability of schizophrenia. We leveraged quantitative trait loci and chromatin interaction profiles to identify schizophrenia risk variants assigned to the genes that represent different transcriptomic features. We then performed stratified linkage disequilibrium score regression analysis on these variants to estimate schizophrenia heritability enrichment for different gene expression features. Notably, DEGs and co-expression networks showed nominal heritability enrichment. This nominal association can be partly explained by cellular heterogeneity, as DEGs were associated with the genetic risk of schizophrenia in a cell type-specific manner. Moreover, DEGs were enriched for target genes of schizophrenia-associated transcription factors, suggesting that the transcriptomic signatures of schizophrenia are the result of transcriptional regulatory cascades elicited by genetic risk factors.
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影响因子：
15.9
作者：
Lewis DA;Curley AA;Glausier JR;Volk DW
通讯作者：
Volk DW
影响因子：
30.8
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Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
DOI：
10.1038/nrn.2016.27
发表时间：
2016-05
期刊：
Nature reviews. Neuroscience
影响因子：
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作者：
Vuong CK;Black DL;Zheng S
通讯作者：
Zheng S
影响因子：
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作者：
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通讯作者：
Wang, Kai
影响因子：
30.8
作者：
Pardiñas AF;Holmans P;Pocklington AJ;Escott-Price V;Ripke S;Carrera N;Legge SE;Bishop S;Cameron D;Hamshere ML;Han J;Hubbard L;Lynham A;Mantripragada K;Rees E;MacCabe JH;McCarroll SA;Baune BT;Breen G;Byrne EM;Dannlowski U;Eley TC;Hayward C;Martin NG;McIntosh AM;Plomin R;Porteous DJ;Wray NR;Caballero A;Geschwind DH;Huckins LM;Ruderfer DM;Santiago E;Sklar P;Stahl EA;Won H;Agerbo E;Als TD;Andreassen OA;Bækvad-Hansen M;Mortensen PB;Pedersen CB;Børglum AD;Bybjerg-Grauholm J;Djurovic S;Durmishi N;Pedersen MG;Golimbet V;Grove J;Hougaard DM;Mattheisen M;Molden E;Mors O;Nordentoft M;Pejovic-Milovancevic M;Sigurdsson E;Silagadze T;Hansen CS;Stefansson K;Stefansson H;Steinberg S;Tosato S;Werge T;GERAD1 Consortium;CRESTAR Consortium;Collier DA;Rujescu D;Kirov G;Owen MJ;O'Donovan MC;Walters JTR
通讯作者：
Walters JTR