A novel genetic variant potentially altering the expression of MANBA in the cerebellum associated with attention deficit hyperactivity disorder in Han Chinese children

Abstract

Objectives

To obtain additional insight into the genetic factors of attention deficit hyperactivity disorder (ADHD).

Methods

First, we performed a transcriptome-wide association study (TWAS) integrating human cerebellum-specific variant-expression/splicing correlations to identify ADHD susceptibility genes. Then, the associations between expression/splicing quantitative trait loci (eQTLs/sQTLs) of the transcriptome-wide significant genes and ADHD were observed in a case-control study of Han Chinese children. Furthermore, dual luciferase reporter gene assays were performed to validate the regulatory function of ADHD risk variants. Additionally, the transcription level of target genes in blood was detected by real-time quantitative polymerase chain reaction (RT-qPCR) assay.

Results

TWAS identified that the genetically regulated expression of MANBA in the cerebellum was significantly associated with ADHD risk. Furthermore, we observed a higher risk of ADHD and more severe clinical symptoms in subjects harbouring heterozygous (TC) or mutant homozygous (TT) genotypes of MANBA rs1054037 than CC carriers. The dual luciferase reporter gene assay revealed that the mutation of rs1054037(C > T) potentially upregulated MANBA expression by eliminating the binding site for hsa-miR-5591-3P. Finally, RT-qPCR showed that MANBA expression in blood samples of patients was significantly higher than that of controls.

Conclusions

Taken together, these results suggest a role of MANBA in the development of ADHD.

Keywords:

• Attention deficit hyperactivity disorder
• transcriptome-wide association study
• MANBA
• genetic association
• transcriptional regulation

Acknowledgments

The authors would like to thank all patients and healthy controls for their voluntary participation in the present study and the authors of the original studies for providing their data in a public manner, making the bioinformatics analysis possible in this study.

Author contributions

Xinzhen Chen: Study design, Data analysis, Interpretation of the results, Original manuscript preparation. Ting Yao, Xihang Fu and Huiru Li: Data collection, Genotyping, Ting Yao, Jinliang Cai and Shanyawen Li: Functional experiments. Qi Zhang: Study design, Data validation. Jing Wu: Study design, Draft revision. All authors approved the final version of the manuscript. The corresponding author attests that all the listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Statement of interest

The authors declared no conflict of interest.

Additional information

Funding

All the authors in this work gratefully acknowledge the financial support by the National Natural Science Foundation of China [grant numbers 8177 3456] to Dr. Jing Wu.