Brain Expressed microRNAs Implicated in Schizophrenia Etiology

Abstract

BackgroundProtein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.Methodology/Principal FindingsWe have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.Conclusions/SignificanceWe found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…Most importantly, the Norwegian patients are generally younger with a shorter duration of illness than the considerably more chronic and poorer outcome of the Danish patients. 22 In the total sample (German, Danish and Norwegian), the association between SREBF1 and schizophrenia was stronger than in the German sample alone (allelic P-value = 0.017-0.0015; Table 2). The markers rs11654081 and rs11868035 are in strong LD (D 0 = 1 and r 2 = 0.75, see Supplementary Figure 1_SREBF1) and so are the markers rs9907246, rs7503334 and rs7222480 (D 0 = 0.99-1 and r 2 = 0.97-0.99).…”

“…21 We did not find any evidence of CNVs in the SREBF1 and SREBF2 genes. 22 The Norwegian Scientific-Ethical Committees, the Norwegian Data Protection Agency, the Danish Scientific Committees, and the Danish Data Protection Agency all approved the study. All patients have given written informed consent before inclusion into the project.…”

The impact of microRNAs and alternative splicing in pharmacogenomics

“…Polymorphisms in miRNA target sites of protein-coding genes that are associated to cancer, [58][59][60] hypertension, 61 asthma, 62 cardiovascular disease 63 and polymorphisms in microRNAs that are associated with schizophrenia 40 were also described.…”

“…62 In cardiovascular disease, Martin et al 63 reported an association of the human angiotensin II type 1 receptor polymorphism and miR-155. Finally, Hansen et al 40 identified important associations between brain-expressed miRNAs and schizophrenia for two SNPs located in mir-206 and mir-198 sequences. Noteworthy is the fact that these miRNAs have a surprisingly large number of targets in common, eight of which are connected by the same transcription factors.…”

“…Noteworthy is the fact that these miRNAs have a surprisingly large number of targets in common, eight of which are connected by the same transcription factors. 40 There is also a study showing that variations within the mir-433 target site of the gene FGF20 increases the risk of Parkinson's disease by increasing the levels of the protein a-synuclein. 28 Finally, polymorphisms in the precursor microRNA can affect the biogenesis and processing which will then result in altered control of gene expression.…”