MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome - PubMed (original) (raw)

MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome

Daniele Merico et al. Front Neurol. 2014.

Abstract

The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes, and those implicated by DGCR8, to identify targets that may be involved in the risk for schizophrenia. The 22q11.2 region encompasses seven validated or putative miRNA genes. Employing two standard prediction tools, we generated sets of predicted target genes. Functional enrichment profiles of the 22q11.2 region miRNA target genes suggested a role in neuronal processes and broader developmental pathways. We then constructed a protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function, independent of the 22q11.2 region miRNA mechanisms. We found that the predicted gene targets of the 22q11.2 deletion miRNAs, and targets of the genome-wide miRNAs predicted to be dysregulated by DGCR8 hemizygosity, were significantly represented in this schizophrenia network. The findings provide new insights into the pathway from 22q11.2 deletion to expression of schizophrenia, and suggest that hemizygosity of the 22q11.2 region may have downstream effects implicating genes elsewhere in the genome that are relevant to the general schizophrenia population. These data also provide further support for the notion that robust genetic findings in schizophrenia may converge on a reasonable number of final pathways.

Keywords: 22q11 deletion; 22q11.2; DGCR8; DiGeorge syndrome; miRNA; protein interaction network; schizophrenia; synapse.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Schematic of miRNAs and the miRNA-processing gene DGCR8 in the 22q11.2 deletion region (genome build GRCh37/hg19). Affymetrix Human SNP Array 6.0 22q11.2 deletion breakpoints are shown (31). Gene and miRNA sizes are enlarged for illustrative purposes and are not to scale. FISH, fluorescence in situ hybridization; LCR, low copy repeats.

Figure 2

Figure 2

Top functional gene-sets enriched in predicted targets of miRNAs from the 22q11.2 deletion region. Enriched gene-sets are visualized as a network, where circles represent gene-sets and connections (lines) depict gene-set overlap; in this way, gene-sets that have a similar gene composition cluster into functional groups, which were manually identified and labeled (light yellow shades if neurobiologically related, and gray shades otherwise; more details can be found in Table S1 in Supplementary Material). Circle colors represent gene-set enrichment of results for six different miRNAs, with yellow representing enrichment in more than one miRNA; black circle border denotes enrichment Benjamini–Hochberg FDR ≤ 25% or enrichment in more than one miRNA. Circle size relates to the total number of genes in the gene-set. This visualization was created using the Cytoscape plugin Enrichment Map (version 1.2).

Figure 3

Figure 3

(A,B) Overlap of 22q11.2 deletion region miRNA-related mechanisms with a physical protein–protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function. The network is composed of 449 genes (78 schizophrenia candidates and 371 interaction partners relevant to brain function; see text and Table S2 in Supplementary Material), depicted as circles, and 773 physical protein–protein interactions, depicted as connecting lines. Genes are colored according to the overlap with 22q11.2 deletion region miRNA deregulation mechanism: (i) predicted targets of the six 22q11.2 miRNAs have color violet if they overlap with curated schizophrenia candidates used to seed the network, and orange otherwise; (ii) predicted targets of at least two miRNAs down-regulated in a model of decreased DGCR8 processing mechanism, excluding predicted targets of the six 22q11.2 miRNAs, have color green if they overlap with curated schizophrenia candidates used to seed the network, and yellow otherwise. Other schizophrenia candidate genes have color blue, while the remainder of the genes have color gray. The densely connected network core corresponding to GRIAs, GRIKs, GRINs, DLGs, DLGAPs, SHANKs, and HOMERs is highlighted by an olive green shade. Gene names are highlighted in boxes for 22q11.2 deletion region miRNA target genes that overlap schizophrenia candidate genes (A), and for target genes of miRNAs implicated by a decreased DGCR8 processing mechanism that overlap schizophrenia candidate genes, as well as a selected subset of other genes of interest for schizophrenia (B).

Figure 3

Figure 3

(A,B) Overlap of 22q11.2 deletion region miRNA-related mechanisms with a physical protein–protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function. The network is composed of 449 genes (78 schizophrenia candidates and 371 interaction partners relevant to brain function; see text and Table S2 in Supplementary Material), depicted as circles, and 773 physical protein–protein interactions, depicted as connecting lines. Genes are colored according to the overlap with 22q11.2 deletion region miRNA deregulation mechanism: (i) predicted targets of the six 22q11.2 miRNAs have color violet if they overlap with curated schizophrenia candidates used to seed the network, and orange otherwise; (ii) predicted targets of at least two miRNAs down-regulated in a model of decreased DGCR8 processing mechanism, excluding predicted targets of the six 22q11.2 miRNAs, have color green if they overlap with curated schizophrenia candidates used to seed the network, and yellow otherwise. Other schizophrenia candidate genes have color blue, while the remainder of the genes have color gray. The densely connected network core corresponding to GRIAs, GRIKs, GRINs, DLGs, DLGAPs, SHANKs, and HOMERs is highlighted by an olive green shade. Gene names are highlighted in boxes for 22q11.2 deletion region miRNA target genes that overlap schizophrenia candidate genes (A), and for target genes of miRNAs implicated by a decreased DGCR8 processing mechanism that overlap schizophrenia candidate genes, as well as a selected subset of other genes of interest for schizophrenia (B).

Similar articles

Cited by

References

    1. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol (2005) 6:376–85.10.1038/nrm1644 - DOI - PubMed
    1. Maffioletti E, Tardito D, Gennarelli M, Bocchio-Chiavetto L. Micro spies from the brain to the periphery: new clues from studies on microRNAs in neuropsychiatric disorders. Front Cell Neurosci (2014) 8:75.10.3389/fncel.2014.00075 - DOI - PMC - PubMed
    1. Bassett AS, McDonald-McGinn DM, Devriendt K, Digilio MC, Goldenberg P, Habel A, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr (2011) 159(332–9):e1.10.1016/j.jpeds.2011.02.039 - DOI - PMC - PubMed
    1. Costain G, McDonald-McGinn DM, Bassett AS. Prenatal genetic testing with chromosomal microarray analysis identifies major risk variants for schizophrenia and other later-onset disorders. Am J Psychiatry (2013) 170:1498.10.1176/appi.ajp.2013.13070880 - DOI - PMC - PubMed
    1. Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med (2011) 13:777–84.10.1097/GIM.0b013e31822c79f9 - DOI - PMC - PubMed

LinkOut - more resources