Functional Genomics Identify a Regulatory Risk Variation rs4420550 in the 16p11.2 Schizophrenia-Associated Locus

KIZ OpenIR > 科研部门 > 转化基因组（李明）

	Functional Genomics Identify a Regulatory Risk Variation rs4420550 in the 16p11.2 Schizophrenia-Associated Locus
	Chang, H; Cai, X; Li, HJ; Liu, WP; Zhao, LJ; Zhang, CY; Wang, JY; Liu, JW; Ma, XL; Wang, L; Yao, YG; Luo, XJ; Li, M; Xiao, X
	2021
发表期刊	BIOLOGICAL PSYCHIATRY
ISSN	0006-3223
卷号	89 期号:3 页码:246-255
摘要	BACKGROUND: Genome-wide association studies (GWASs) have reported hundreds of genomic loci associated with schizophrenia, yet identifying the functional risk variations is a key step in elucidating the underlying mechanisms. METHODS: We applied multiple bioinformatics and molecular approaches, including expression quantitative trait loci analyses, epigenome signature identification, luciferase reporter assay, chromatin conformation capture, homology-directed genome editing by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9), RNA sequencing, and ATAC-Seq (assay for transposase-accessible chromatin using sequencing). RESULTS: We found that the schizophrenia GWAS risk variations at 16p11.2 were significantly associated with messenger RNA levels of multiple genes in human brain, and one of the leading expression quantitative trait loci genes, MAPK3, is located similar to 200 kb away from these risk variations in the genome. Further analyses based on the epigenome marks in human brain and cell lines suggested that a noncoding single nucleotide polymorphism, rs4420550 (p = 2.36 x 10(-9) in schizophrenia GWAS), was within a DNA enhancer region, which was validated via in vitro luciferase reporter assays. The chromatin conformation capture experiment showed that the rs4420550 region physically interacted with the MAPK3 promoter and TAOK2 promoter. Precise CRISPR/Cas9 editing of a single base pair in cells followed by RNA sequencing further confirmed the regulatory effects of rs4420550 on the transcription of 16p11.2 genes, and ATAC-Seq demonstrated that rs4420550 affected chromatin accessibility at the 16p11.2 region. The rs4420550-[A/A] cells showed significantly higher proliferation rates compared with rs4420550-[G/G] cells. CONCLUSIONS: These results together suggest that rs4420550 is a functional risk variation, and this study illustrates an example of comprehensive functional characterization of schizophrenia GWAS risk loci.
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/152453/13730
专题	科研部门_转化基因组（李明）
推荐引用方式 GB/T 7714	Chang, H,Cai, X,Li, HJ,et al. Functional Genomics Identify a Regulatory Risk Variation rs4420550 in the 16p11.2 Schizophrenia-Associated Locus[J]. BIOLOGICAL PSYCHIATRY,2021,89(3):246-255.
APA	Chang, H.,Cai, X.,Li, HJ.,Liu, WP.,Zhao, LJ.,...&Xiao, X.(2021).Functional Genomics Identify a Regulatory Risk Variation rs4420550 in the 16p11.2 Schizophrenia-Associated Locus.BIOLOGICAL PSYCHIATRY,89(3),246-255.
MLA	Chang, H,et al."Functional Genomics Identify a Regulatory Risk Variation rs4420550 in the 16p11.2 Schizophrenia-Associated Locus".BIOLOGICAL PSYCHIATRY 89.3(2021):246-255.

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