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A new locus regulating MICALL2 expression was identified for association with executive inhibition in children with attention deficit hyperactivity disorder

Molecular Psychiatry volume 23, pages 1014–1020 (2018)Cite this article

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Abstract

Impaired executive inhibition is a core deficit of attention deficit hyperactivity disorder (ADHD), which is a common childhood-onset psychiatric disorder with high heritability. In this study, we performed a two-stage genome-wide association study of executive inhibition in ADHD in Han Chinese. We used the Stroop color-word interference test to evaluate executive inhibition. After quality control, 780 samples with phenotype and covariate data were included in the discovery stage, whereas 922 samples were included in the replication stage. We identified one new significant locus at 7p22.3 for the Stroop word interference time (rs11514810, P=3.42E−09 for discovery, P=0.01176 for replication and combined P=5.249E−09). Regulatory feature analysis and expression quantitative trait loci (eQTL) data showed that this locus contributes to MICALL2 expression in the human brain. Most genes in the network interacting with MICALL2 were associated with psychiatric disorders. Furthermore, hyperactive-impulsive-like behavior was induced by reducing the expression of the zebrafish gene that is homologous to MICALL2, which could be rescued by tomoxetine (atomoxetine), a clinical medication for ADHD. Our results suggested that MICALL2 is a new susceptibility gene for executive inhibition deficiency related to hyperactive-impulsive behavior in ADHD, further emphasizing the possible role of neurodevelopmental genes in the pathogenic mechanism of ADHD.

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Acknowledgements

We thank all the patients for participating in this study. This work was supported by grants from the Major State Basic Research Development Program of China (973 Program, 2014CB846100 to YW), the National Natural Science Foundation of China (31401139 to SC, 81471381 to LY, and 31571496 to DL), Beijing Municipal Science and Technology Commission (Z151100003915122), and National Institutes of Health (R01HL129132 and R01HG006292 to YL), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (695313).

Author information

Author notes

  1. L Yang and S Chang: These authors contributed equally to this work.

  2. D Liu, J Wang and Y Wang: These authors jointly supervised this work.

Authors and Affiliations

  1. Peking University Sixth Hospital (Institute of Mental Health), National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China

    L Yang, Q Lu, Z Wu, X Sun, Q Cao, Y Qian, Y Wang & L Lu

  2. CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    S Chang, K Zhang & J Wang

  3. University of Chinese Academy of Sciences, Beijing, China

    S Chang & J Wang

  4. College of Life Science, Peking University, Beijing, China

    Y Zhang

  5. Institute of Psychiatry, King’s College London, London, UK

    T Jia, B Xu & G Schumann

  6. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK

    T Jia, B Xu & G Schumann

  7. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    Q Duan & Y Li

  8. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA

    Y Li

  9. Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA

    Y Li

  10. Department of Biology, Southern University of Science and Technology of China, Guangdong, China,

    D Liu

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Yang, L., Chang, S., Lu, Q. et al. A new locus regulating MICALL2 expression was identified for association with executive inhibition in children with attention deficit hyperactivity disorder. Mol Psychiatry 23, 1014–1020 (2018). https://doi.org/10.1038/mp.2017.74

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