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. 2016 Aug 30;6(8):e879.
doi: 10.1038/tp.2016.151.

Preliminary Evidence for Association of Genetic Variants in pri-miR-34b/c and Abnormal miR-34c Expression With Attention Deficit and Hyperactivity Disorder

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Free PMC article

Preliminary Evidence for Association of Genetic Variants in pri-miR-34b/c and Abnormal miR-34c Expression With Attention Deficit and Hyperactivity Disorder

I Garcia-Martínez et al. Transl Psychiatry. .
Free PMC article

Abstract

Attention deficit and hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by impairment to sustain attention and inability to control impulses and activity level. The etiology of ADHD is complex, with an estimated heritability of 70-80%. Under the hypothesis that alterations in the processing or target binding of microRNAs (miRNAs) may result in functional alterations predisposing to ADHD, we explored whether common polymorphisms potentially affecting miRNA-mediated regulation are involved in this psychiatric disorder. We performed a comprehensive association study focused on 134 miRNAs in 754 ADHD subjects and 766 controls and found association between the miR-34b/c locus and ADHD. Subsequently, we provided preliminary evidence for overexpression of the miR-34c-3p mature form in peripheral blood mononuclear cells of ADHD subjects. Next, we tested the effect on gene expression of single-nucleotide polymorphisms within the ADHD-associated region and found that rs4938923 in the promoter of the pri-miR-34b/c tags cis expression quantitative trait loci for both miR-34b and miR-34c and has an impact on the expression levels of 681 transcripts in trans, including genes previously associated with ADHD. This gene set was enriched for miR-34b/c binding sites, functional categories related to the central nervous system, such as axon guidance or neuron differentiation, and serotonin biosynthesis and signaling canonical pathways. Our results provide preliminary evidence for the contribution to ADHD of a functional variant in the pri-miR-34b/c promoter, possibly through dysregulation of the expression of mature forms of miR-34b and miR-34c and some target genes. These data highlight the importance of abnormal miRNA function as a potential epigenetic mechanism contributing to ADHD.

Conflict of interest statement

MC has received travel grants and research support from Eli Lilly, Janssen-Cilag, Shire and Laboratorios Rubió. He has been on the advisory board and served as a consultant for Eli Lilly, Janssen-Cilag, Shire and Laboratorios Rubió.JAR-Q has served on the speakers' bureau and acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Lundbeck, Shire, Ferrer and Laboratorios Rubió. He has received travel awards from Eli Lilly, Janssen-Cilag and Shire for participating in psychiatric meetings. The ADHD Program chaired by JAR-Q has received unrestricted educational and research support from Eli Lilly, Janssen-Cilag, Shire, Rovi and Laboratorios Rubió in the past 2 years. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Graphical representation of significant cis-eQTL analysis between rs4938723 and 2−ΔΔCT expression values of (a) miR-34b-3p and (b) miR-34c-3p. eQTL, expression quantitative trait locus.
Figure 2
Figure 2
Significantly enriched canonical pathways considering differentially expressed genes identified in the trans-eQTL analysis. Along the x axis of the bar chart, the canonical pathways are shown. Along the left y axis, the statistical significance is indicated as −log(P-value), calculated using the right-tailed Fisher's exact test. Gray bars denote statistical significance of the enrichment for each canonical pathway. The black straight line stands for the threshold above which there is significant enrichment (by default P-value <0.05). Along the right y axis, the ratio parameter is shown, calculated by the numbers of genes in a given pathway that meet cutoff criteria, divided by total numbers of genes that make up that pathway. Black squares express the ratio for each pathway. eQTL, expression quantitative trait locus.
Figure 3
Figure 3
Ingenuity pathway best network (score=37, focus molecules=28) based on the top differentially expressed genes from the trans-eQTL analysis considering the rs4938723T risk variant in the pri-miR-34b/c promoter. Mapped molecules from the data set are represented as nodes with colored background and interacting proteins added from the Ingenuity database correspond to clear background nodes. Molecule over- and under-expression are denoted by light and dark gray coloring, respectively. eQTL, expression quantitative trait locus.

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