Genomic duplication and deletions are known as copy number variants (CNVs). These rare genetic lesions assert their effects by altering gene dosage and modifying transcriptional equilibrium. Where these affect regulators of gene expression, their impact can be more dramatic as they have broader influence. Post-transcriptional regulators known as microRNA (miRNA) can alter the gene expression of many genes and alter gene pathways. We hypothesised that copy number variation associated with complex disorders, such as schizophrenia, may preferentially affect miRNA that regulate pathways associated with the condition. Genome-wide CNV analysis was performed using Illumina 610k Quad SNP arrays on 402 cases of schizophrenia to 271 healthy controls from the Australian Schizophrenia Research Bank. Copy number calling was accomplished with PennCNV and association analysis was performed using PLINK. CNVs and nearby regions associated with schizophrenia (p-value < 0.1) were screened for miRNA genes. The targets for these miRNA were then predicted bioinformatically using TargetScan. Target genes for these miRNA that were encompassed by CNVs associated with schizophrenia were identified. These were then subjected to pathways analysis to explore the functional significance.
This identified 9 genomic regions including: 19q13.2-19q13.31,22q11.23,1p36.33,14q31.33,12p13.31,10q26.3,10q22.1,6p21.33 and 11q25, associated with schizophrenia. Three overlapping miRNA (MIR1236,MIR4710,MIR203) and two nearby miRNA (MIR429,MIR200A) were found to contain 9 predicted protein targets within these genomic regions of interest. These genes were JAG2,SLC2A3, EIF4EBP2,SAR1A,CHST3,RNF5,BAG6,PPT2 and CCNL2. This analysis suggested that pathways associated with miRNA genes affected by CNVs in schizophrenia are related to the biology of the disorder. This also identified target genes of these miRNA within CNVs in the schizophrenia group. More specifically this method identified JAG2, important component within the NOTCH pathway, which controls neurogenesis and SLC2A3, a neuron-specific facilitated glucose transporter. These preliminary findings are of interest as they imply that CNV associated with complex disorders are enriched with functionally related genes and regulatory RNA that may provide useful models of the disorder and predict novel candidate genes and pathways.