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
	Chen, R; Yang, ZH; Liu, JW; Cai, X; Huo, YX; Zhang, ZJ; Li, M; Chang, H; Luo, XJ
	2022
发表期刊	GENOME MEDICINE
ISSN	1756-994X
卷号	14 期号:1
摘要	Background 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. Methods 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. Results 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. Conclusions 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.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13331
专题	科研部门_神经系统疾病（罗雄剑）
推荐引用方式 GB/T 7714	Chen, R,Yang, ZH,Liu, JW,et al. Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants[J]. GENOME MEDICINE,2022,14(1).
APA	Chen, R.,Yang, ZH.,Liu, JW.,Cai, X.,Huo, YX.,...&Luo, XJ.(2022).Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants.GENOME MEDICINE,14(1).
MLA	Chen, R,et al."Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants".GENOME MEDICINE 14.1(2022).

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