Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants.
Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants.
复制标题
功能基因组分析描绘了 GWAS 确定的双相情感障碍风险变异的调节机制
DOI：
10.1186/s13073-022-01057-3
复制
发表时间：
2022-05-20
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
全基因组关联研究(GWAS)已确定双相情感障碍(BD)的多个危险基因。然而，准确定位已报道的风险基因座中的功能性(或因果)变异并阐明其调控机制仍然具有挑战性。我们首次整合了来自人脑组织(或神经细胞系)的染色质免疫沉淀测序(ChIP-Seq)数据和位置权重矩阵(PWM)数据，以识别功能性单核苷酸多态(SNPs)。然后，我们通过一系列实验，包括报告基因分析、等位基因特异性表达(ASE)分析、转录因子(TF)基因敲除、CRISPR/Cas9介导的基因组编辑和表达数量性状位点(EQTL)分析，验证了这些转录因子(TF)结合干扰SNPs(以下简称功能SNPs)的调控作用。最后，我们在小鼠原代皮质神经元中过表达PACS1(其表达与已鉴定的功能SNPs rs10896081和rs3862386最显著相关)，以研究PACS1是否影响树突棘密度。我们发现了16个功能性SNPs(在9个风险基因座上)；这些功能性SNPs干扰了7个TF的结合，例如，CTCF和REST结合经常被破坏。然后，我们通过eQTL分析确定了在人脑中表达受这些功能SNPs调控的潜在靶基因。值得注意的是，与对照组相比，我们发现BD患者中已鉴定的TF结合破坏SNPs的一些靶基因调控异常，并且PACS1的过表达降低了树突棘的密度，揭示了这些功能SNPs在BD中的可能生物学机制。我们的研究确定了一些已报道的风险基因座中的功能性SNPs，并阐明了BD风险变体的调控机制。这些功能SNPs和候选基因的进一步功能特征和机制研究将有助于阐明BD的发病机制，并开发新的治疗方法和药物。网上版载有补充材料，可在10.1186/s13073-022-01057-3查阅。
Genome-wide association studies (GWASs) have identified multiple risk loci for bipolar disorder (BD). However, pinpointing functional (or causal) variants in the reported risk loci and elucidating their regulatory mechanisms remain challenging. We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) data from human brain tissues (or neuronal cell lines) and position weight matrix (PWM) data to identify functional single-nucleotide polymorphisms (SNPs). Then, we verified the regulatory effects of these transcription factor (TF) binding–disrupting SNPs (hereafter referred to as “functional SNPs”) through a series of experiments, including reporter gene assays, allele-specific expression (ASE) analysis, TF knockdown, CRISPR/Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Finally, we overexpressed PACS1 (whose expression was most significantly associated with the identified functional SNPs rs10896081 and rs3862386) in mouse primary cortical neurons to investigate if PACS1 affects dendritic spine density. We identified 16 functional SNPs (in 9 risk loci); these functional SNPs disrupted the binding of 7 TFs, for example, CTCF and REST binding was frequently disrupted. We then identified the potential target genes whose expression in the human brain was regulated by these functional SNPs through eQTL analysis. Of note, we showed dysregulation of some target genes of the identified TF binding–disrupting SNPs in BD patients compared with controls, and overexpression of PACS1 reduced the density of dendritic spines, revealing the possible biological mechanisms of these functional SNPs in BD. Our study identifies functional SNPs in some reported risk loci and sheds light on the regulatory mechanisms of BD risk variants. Further functional characterization and mechanistic studies of these functional SNPs and candidate genes will help to elucidate BD pathogenesis and develop new therapeutic approaches and drugs. The online version contains supplementary material available at 10.1186/s13073-022-01057-3.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
影响因子：
16.2
作者：
Collado-Torres, Leonardo;Burke, Emily E.;Narurkar, Rujuta
通讯作者：
Narurkar, Rujuta
影响因子：
4.5
作者：
Verma SS;Cooke Bailey JN;Lucas A;Bradford Y;Linneman JG;Hauser MA;Pasquale LR;Peissig PL;Brilliant MH;McCarty CA;Haines JL;Wiggs JL;Vrabec TR;Tromp G;Ritchie MD;eMERGE Network;NEIGHBOR Consortium
通讯作者：
NEIGHBOR Consortium
影响因子：
11
作者：
Baum, A. E.;Akula, N.;McMahon, F. J.
通讯作者：
McMahon, F. J.