Researchers reveal the molecular regulatory mechanism in schizophrenia susceptibility locus 2q33.1

A research team led by Prof. LUO Xiongjian from Kunming Institute of Zoology of the Chinese Academy of Sciences reported the regulatory variants at 2q33.1 confer schizophrenia risk by modulating distal gene TYW5 expression. The finding was published in Brain on 28th September, 2021. 

Schizophrenia, the heritability around 79-81%, is a severe and chronic psychiatric disorder with about 1% lifetime prevalence. To date, despite the fact genome-wide association studies (GWASs) have identified more than one hundred susceptibility loci and provided important insights into the genetic factors of schizophrenia, elucidating the genetic and pathogenic mechanisms of the reported susceptibility loci in schizophrenia remain a challenge in post-GWAS era. 

Multiple GWASs showed that genetic variants at 2q33.1 were strongly associated with schizophrenia and the previous functional genomics study had identified two functional SNPs (rs796364, rs281759) in this locus. However, the roles of these functional variants in schizophrenia remain unknown.  

In the published study, researchers conducted serial functional experiments and found that the molecular regulation mechanism of these variants (disrupting CTCF, RAD21 and FOXP2 binding) confer schizophrenia by modulating distal gene TYW5 expression.

In the published human brain expression data, they found that TYW5 was significantly up-regulated in schizophrenia patients. Further through the experiments of neural stem cells and neurons, they observed that overexpression of TYW5 affected neurodevelopment and dendritic spines formation. No surprising, they also found that rs796364 is a schizophrenia associated variants in Chinese population in their independent genetic association study.  

In combination with the published intelligence and cognitive function GWASs data, they observed that rs796364 was significantly associated with intelligence and cognitive function and the risk allele of rs796364 with poorer cognitive performance. Thus, they identified that rs796364 may be a true causal variant in schizophrenia.  

In summary, this study revealed that two functional variants at 2q33.1 confer schizophrenia through disrupting TFs binding to modulated distal gene TYW5 expression, these findings would help people to further understand the genetic basis of 2q33.1 in schizophrenia. 

This study, entitled Regulatory variants at 2q33.1 confer schizophrenia risk by modulating distal gene TYW5 expression, was published in Brain on 28th September, 2021. Web link: https://doi.org/10.1093/brain/awab357). Dr. LUO Xiongjian is the corresponding author, Dr. LI Shiwu, LI Jiao and Dr. LIU Jiewei are co-first authors in this paper 

This study was financially supported by the Key Research Project of Yunnan Province (202101AS070055) , the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17), the Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004), the Distinguished Young Scientists grant of the Yunnan Province (202001AV070006), the National Nature Science Foundation of China (31970561), the Western Light Innovative Research Team of Chinese Academy of Sciences, and the Western Light Program of Chinese Academy of Sciences.

 

Figure 1Insight of molecular regulatory mechanism in schizophrenia susceptibility locus 2q33.1 

 

(By LUO Xiongjian, Editor:YANG Yingrun )

 

Contact:

LUO Xiongjian

luoxiongjian@mail.kiz.ac.cn

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