Abstract
Despite much progress, few genetic findings for schizophrenia have been assessed by functional validation experiments at the molecular level. We previously reported evidence for genetic linkage of broadly defined schizophrenia to chromosome 17q25 in a sample of 24 multiplex families. 2,002 SNPs under this linkage peak were analyzed for evidence of linkage disequilibrium using the posterior probability of linkage (PPL) framework. SNP rs1060120 produced the strongest evidence for association, with a PPLD|L score of 0.21. This SNP is located within the 3'UTR of the histone gene H3F3B and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to H3F3B transcripts would be altered by the allelic variants of rs1060120. We used dual luciferase assays to experimentally validate this interaction. The rs1060120 A allele significantly reduced luciferase expression, indicating a stronger interaction with miR-616 than the G allele (p = 0.000412). These results provide functional validation that this SNP could alter schizophrenia epigenetic mechanisms thereby contributing to schizophrenia-related disease risk.
Highlights
Schizophrenia is a complex disorder that is believed to be caused by the interaction of multiple genetic risk factors, within and between individuals
A total of five MirSNPs were predicted from the 17q25 region of this linkage peak, chr17: 74,684,647 to 83,257,441 (GRCh38): rs1060120 in gene H3F3B, rs4969391 in gene BAIAP2, rs7211218 in predicted gene LOC283999, rs1663196 in gene TBC1D16, and rs1128687 in gene CHMP6 (Table 1)
Using the broad schizophrenia spectrum phenotype, PPLD|L values were calculated for 1,540 SNPs from the Affymetrix 6.0 Array and the five MirSNPs
Summary
Schizophrenia is a complex disorder that is believed to be caused by the interaction of multiple genetic risk factors, within and between individuals. This work has indicated a high genetic correlation between schizophrenia and bipolar disorder and a moderate genetic correlation between schizophrenia and major depressive disorder[2] In other studies, both common risk alleles of low effect size and rare mutations of high effect size have been shown to contribute to schizophrenia and to other psychiatric disorders [2,3,4]. Both common risk alleles of low effect size and rare mutations of high effect size have been shown to contribute to schizophrenia and to other psychiatric disorders [2,3,4] These risk variants appear to cluster in functional gene sets involving genes that cause alterations in the regulation of gene expression in the brain[5,6], genes important for calcium channels and glutamatergic synapses [7,8,9], and genes that alter the expression profiles of miRNAs[10,11,12,13,14,15,16,17]
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