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Researchers Illustrate Multiple Functional Variations Correlated with the Heritable Risk of Schizophrenia
2021-02-24 | Author: | From:

Complex psychiatric illnesses, such as schizophrenia, are bringing significant threat to public well-being, yet clinical diagnosis and management of these illnesses remain less successful due to a lack of knowledge of their pathogenesis. Recent genome-wide association studies (GWAS) have identified numerous non-coding variations significantly associated with schizophrenia, but the potential biological impact of these variations is yet to be elucidated. 

For example, common variations in the chromosome 16p11.2 region have been found to be significantly associated with the risk of schizophrenia, but further functional explorations for the underlying molecular mechanisms are needed. We have performed integrative analyses of the publicly available human brain expression quantitative trait loci (eQTL) and chromatin immunoprecipitation sequencing (ChIP-Seq) of histone modification datasets, and found significant enrichment of epigenetic modifiers at the single nucleotide polymorphism (SNP) rs4420550 of 16p11.2, indicating regulatory impact of this variation on gene transcription, explaining its association with the mRNA expression of MAPK3. However, rs4420550 locates 200kb away from the MAPK3 gene. Whether this variation exerts distal regulatory effects on gene transcription is of great interest for further investigation.

The ChIP-Seq results of rs4420550 in brain tissues and cell lines suggested that this variation likely resided in the enhancer region of the genome. Dual luciferase activity assays further confirmed this hypothesis. We then performed chromosome conformation capture (3C) assay, and found that rs4420550 directly interacted with the promoter of MAPK3. Meanwhile, we have also obtained homozygotic cell clones carrying either G/G or A/A genotypes at rs4420550 via homology directed repair (HDR)-directed genome editing by CRISPR/Cas9 (Figure 1), and confirmed through RNA sequencing (RNA-seq) and assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAQ-seq) that different alleles of this variation resulted in altered expression of multiple genes including MAPK3. Intriguingly, cells carrying different homozygotic alleles at rs4420550 exhibited significantly different proliferation rates.

 

Figure 1. HDR-directed genome editing by CRISPR/Cas9 of rs4420550 in cells.

(Imaged by HONG Chang and XIAO Xiao) 

 

This study identified a common genetic variation affecting cell proliferation and heritable risk of schizophrenia, which regulates transcription as an enhancer element. As one of the few examples of the complicated distal transcription regulation in schizophrenia, this study, entitled “Functional genomics identify a regulatory risk variation rs4420550 in the 16p11.2 schizophrenia-associated locus” , was published in Biological Psychiatry on September 22, 2020. Web link: https://www.sciencedirect.com/science/article/abs/pii/S0006322320319247). Dr. CHANG Hong, CAI Xin (PHD student at KIZ) and LI Huijuan (PHD student at KIZ) are co-first authors of this work. Dr. XIAO Xiao and Dr. LI Ming are corresponding authors. Dr. LUO Xiongjian and Dr. YAO Yonggang have provided constructive help and support. This study was financially supported by grants from the National Natural Science Foundation of China and the Strategic Priority Research Program of the Chinese Academy of Sciences.

 

 

(By LI Ming, Editor: YANG Yingrun)

Contact:

YANG Yingrun

yangyingrun@mail.kiz.ac.cn

Adress:No.32 Jiaochang Donglu Kunming 650223 Yunnan, China Tel:86-871-65197869