Abstract

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40–65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA–mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.

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Acknowledgements

The authors are grateful to patients and controls who kindly participated in this research. The miRNA sequencing service was carried out at the Centre for Genomic Regulation (CRG), Barcelona, Spain. The microarrays service was carried out at High Technology Unit (UAT) at Vall d’Hebron Research Institute (VHIR), Barcelona (Spain), and the Statistics and Bioinformatics Unit (UEB) at the VHIR provided statistical support.

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Affiliations

  1. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain

    • Cristina Sánchez-Mora
    • , María Soler Artigas
    • , Iris Garcia-Martínez
    • , Mireia Pagerols
    • , Paula Rovira
    • , Miguel Casas
    • , Josep-Antoni Ramos-Quiroga
    •  & Marta Ribasés
  2. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain

    • Cristina Sánchez-Mora
    • , María Soler Artigas
    • , Iris Garcia-Martínez
    • , Mireia Pagerols
    • , Paula Rovira
    • , Vanesa Richarte
    • , Montse Corrales
    • , Christian Fadeuilhe
    • , Miguel Casas
    • , Josep-Antoni Ramos-Quiroga
    •  & Marta Ribasés
  3. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    • Cristina Sánchez-Mora
    • , María Soler Artigas
    • , Vanesa Richarte
    • , Montse Corrales
    • , Miguel Casas
    • , Josep-Antoni Ramos-Quiroga
    •  & Marta Ribasés
  4. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain

    • Vanesa Richarte
    • , Montse Corrales
    • , Miguel Casas
    •  & Josep-Antoni Ramos-Quiroga
  5. Research Unit in Clinical and Translational Bioinformatics, Vall d’Hebron Institute of Research (VHIR), Barcelona, Spain

    • Natàlia Padilla
    •  & Xavier de la Cruz
  6. Universitat Autònoma de Barcelona, Barcelona, Spain

    • Natàlia Padilla
    •  & Xavier de la Cruz
  7. ICREA, Barcelona, Spain

    • Xavier de la Cruz
  8. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    • Barbara Franke
    •  & Alejandro Arias-Vásquez
  9. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    • Barbara Franke
    •  & Alejandro Arias-Vásquez

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https://doi.org/10.1038/s41386-018-0297-0