Validation of a microRNA target site polymorphism in <i>H3F3B</i> that is potentially associated with a broad schizophrenia phenotype

<div><p>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 <i>H3F3B</i> and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to <i>H3F3B</i> 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.</p></div

Linkage disequilibrium between 1,544 SNPs and broad schizophrenia spectrum phenotype.

<p>PPLD|L values for 1,544 SNPs, including five MirSNPs (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194233#pone.0194233.t001" target="_blank">Table 1</a>), from chr17: 74,684,647 to 83,257,441 (GRCh38), were calculated using KELVIN v2.4.0 and plotted vs physical distance. The MirSNP rs1060120 in <i>H3F3B</i> produced a PPLD|L of 0.21, notably higher than the remaining SNPs.</p

Predicted MirSNPs from the chromosome 17q25 region of association/linkage to broadly defined schizophrenia.

<p>Predicted MirSNPs from the chromosome 17q25 region of association/linkage to broadly defined schizophrenia.</p