Original Article | Published:

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 10141020 (2018) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , , . The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007; 164: 942–948.

  2. 2.

    , , , , , et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313–1323.

  3. 3.

    , , . Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 2009; 126: 51–90.

  4. 4.

    , , , . Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 2006; 15: 2276–2284.

  5. 5.

    , , , , , et al. Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol Psychiatry 2006; 59: 460–467.

  6. 6.

    , , , , . The IMAGE project: methodological issues for the molecular genetic analysis of ADHD. Behav Brain Funct 2006; 2: 27.

  7. 7.

    , , , , , et al. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am J Med Genet B 2013; 162B: 419–430.

  8. 8.

    , , , , , et al. Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49: 884–897.

  9. 9.

    , , , , , et al. Genome-wide association study in German patients with attention deficit/hyperactivity disorder. Am J Med Genet B 2011; 156B: 888–897.

  10. 10.

    , , , , , et al. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am J Psychiatry 2012; 169: 186–194.

  11. 11.

    , , , . Testing for neuropsychological endophenotypes in siblings discordant for attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 62: 991–998.

  12. 12.

    , , , , , et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249–264.

  13. 13.

    , , , . Association of interleukin-10 polymorphisms with schizophrenia: a meta-analysis. PLoS ONE 2014; 9: e90407.

  14. 14.

    , . Moderators of neuropsychological mechanism in attention-deficit hyperactivity disorder. J Abnorm Child Psychol 2015; 43: 271–281.

  15. 15.

    , , , . The persistence of cognitive deficits in remitted and unremitted ADHD: a case for the state-independence of response inhibition. J Child Psychol Psychiatry 2014; 55: 292–300.

  16. 16.

    , . Executive functions and developmental psychopathology. J Child Psychol Psychiatry 1996; 37: 51–87.

  17. 17.

    . Attention-deficit/hyperactivity disorder, self-regulation, and time: toward a more comprehensive theory. J Dev Behav Pediatr 1997; 18: 271–279.

  18. 18.

    , . Storage and executive processes in the frontal lobes. Science 1999; 283: 1657–1661.

  19. 19.

    , , , , , . The unity and diversity of executive functions and their contributions to complex 'Frontal Lobe' tasks: a latent variable analysis. Cogn Psychol 2000; 41: 49–100.

  20. 20.

    , , , , , . Executive dysfunctions in children with attention deficit hyperactivity disorder. Int J Neurosci 1998; 96: 177–196.

  21. 21.

    . Attention-Deficit Hyperactivity Disorder (Third Edition): A Handbook for Diagnosis and Treatment. The Guilford Press: New York, NY, USA, 2006.

  22. 22.

    . Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 1997; 121: 65–94.

  23. 23.

    , , , . Evaluating the endophenotype model of ADHD neuropsychological deficit: results for parents and siblings of children with ADHD combined and inattentive subtypes. J Abnorm Psychol 2004; 113: 614–625.

  24. 24.

    , , , . Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry 2007; 12: 502–509.

  25. 25.

    , , , , , et al. Both the COMT Val158Met single-nucleotide polymorphism and sex-dependent differences influence response inhibition. Front Behav Neurosci 2015; 9: 127.

  26. 26.

    , , , , , et al. Identifying mechanisms that underlie links between COMT genotype and aggression in male adolescents with ADHD. J Child Psychol Psychiatry 2016; 57: 472–480.

  27. 27.

    , , , , , et al. The role of age in association analyses of ADHD and related neurocognitive functioning: a proof of concept for dopaminergic and serotonergic genes. Am J Med Genet B 2015; 168: 471–479.

  28. 28.

    , , , , , et al. Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls. World J Biol Psychiatry 2015; 16: 625–634.

  29. 29.

    , , , , , et al. Testing differential susceptibility: plasticity genes, the social environment, and their interplay in adolescent response inhibition. World J Biol Psychiatry advance online publication, 12 May 2016, 1–14; doi: 10.3109/15622975.2016.1173724.

  30. 30.

    , , , , , et al. Alpha-2A adrenergic receptor gene variants are associated with increased intra-individual variability in response time. Mol Psychiatry 2014; 19: 1031–1036.

  31. 31.

    , , , , . DSM-IV subtypes of ADHD in a Chinese outpatient sample. J Am Acad Child Adolesc Psychiatry 2004; 43: 248–250.

  32. 32.

    , , . Population structure and eigenanalysis. PLoS Genet 2006; 2: e190.

  33. 33.

    , , , , , . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

  34. 34.

    , , , , , et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren's syndrome at 7q11.23. Nat Genet 2013; 45: 1361–1365.

  35. 35.

    , , , , , et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

  36. 36.

    , , , . MaCH-admix: genotype imputation for admixed populations. Genet Epidemiol 2013; 37: 25–37.

  37. 37.

    Genomes Project CGenomes Project C, Genomes Project C, Genomes Project C, Genomes Project C, Genomes Project C et al. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491: 56–65.

  38. 38.

    , , , . Genotype imputation. Annu Rev Genomics Hum Genet 2009; 10: 387–406.

  39. 39.

    , , , . rVarBase: an updated database for regulatory features of human variants. Nucleic Acids Res 2016; 44: D888–893.

  40. 40.

    , , , , , et al. Architecture of the human regulatory network derived from ENCODE data. Nature 2012; 489: 91–100.

  41. 41.

    , , , , , et al. Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies. J Neurochem 2011; 119: 275–282.

  42. 42.

    , , , , , et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 2014; 17: 1418–1428.

  43. 43.

    , , , , , et al. PINA v2.0: mining interactome modules. Nucleic Acids Res 2012; 40: D862–D865.

  44. 44.

    , , , , , et al. A human phenome-interactome network of protein complexes implicated in genetic disorders. Nat Biotechnol 2007; 25: 309–316.

  45. 45.

    , , , , , et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 2010; 38: W214–W220.

  46. 46.

    . Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach. Guilford Press: New York, USA, 2013.

  47. 47.

    , , , , . MICALs a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 2002; 109: 887–900.

  48. 48.

    , , , , , et al. ADHD gene: a genetic database for attention deficit hyperactivity disorder. Nucleic Acids Res 2012; 40: D1003–D1009.

  49. 49.

    , , , . SZGR: a comprehensive schizophrenia gene resource. Mol Psychiatry 2010; 15: 453–462.

  50. 50.

    , , , , , . MK4MDD: a multi-level knowledge base and analysis platform for major depressive disorder. PLoS ONE 2012; 7: e46335.

  51. 51.

    , , , , . Drosophila MICAL regulates myofilament organization and synaptic structure. Mech Dev 2007; 124: 390–406.

  52. 52.

    , , . Rab13 regulates neurite outgrowth in PC12 cells through its effector protein, JRAB/MICAL-L2. Mol Cell Biol 2010; 30: 1077–1087.

  53. 53.

    , , , , . JRAB/MICAL-L2 is a junctional Rab13-binding protein mediating the endocytic recycling of occludin. Mol Biol Cell 2006; 17: 2465–2475.

  54. 54.

    , . Cell-surface biotinylation to study endocytosis and recycling of occludin. Methods Mol Biol 2008; 440: 89–96.

  55. 55.

    , . Identification and characterization of JRAB/MICAL-L2, a junctional Rab13-binding protein. Methods Enzymol 2008; 438: 141–153.

  56. 56.

    , , , , , . A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients. Mol Psychiatry 2000; 5: 172–180.

  57. 57.

    , , . Executive function profile of Chinese boys with attention-deficit hyperactivity disorder: different subtypes and comorbidity. Archiv Clin Neuropsychol 2011; 26: 120–132.

  58. 58.

    , , , , . Heritability of response inhibition in children. J Int Neuropsychol Soc 2011; 17: 238–247.

  59. 59.

    , , , , , et al. Inhibition of motor responses in siblings concordant and discordant for attention deficit hyperactivity disorder. Am J Psychiatry 2005; 162: 1076–1082.

  60. 60.

    , , , , , . Support for an independent familial segregation of executive and intelligence endophenotypes in ADHD families. Psychol Med 2008; 38: 1595–1606.

Download references

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

    • L Yang
    •  & S Chang

    These authors contributed equally to this work.

    • D Liu
    • , J Wang
    •  & Y Wang

    These authors jointly supervised this work.

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

Authors

  1. Search for L Yang in:

  2. Search for S Chang in:

  3. Search for Q Lu in:

  4. Search for Y Zhang in:

  5. Search for Z Wu in:

  6. Search for X Sun in:

  7. Search for Q Cao in:

  8. Search for Y Qian in:

  9. Search for T Jia in:

  10. Search for B Xu in:

  11. Search for Q Duan in:

  12. Search for Y Li in:

  13. Search for K Zhang in:

  14. Search for G Schumann in:

  15. Search for D Liu in:

  16. Search for J Wang in:

  17. Search for Y Wang in:

  18. Search for L Lu in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to D Liu or J Wang or Y Wang.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/mp.2017.74

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Further reading