Allele-specific regulation of DISC1 expression by miR-135b-5p

Disrupted-in-schizophrenia-1 ( DISC1) gene has been established as a risk factor for various neuropsychiatric phenotypes. Both coding and regulatory variants in DISC1have been identified and associated with these phenotypes in genetic studies. MicroRNAs (miRNAs) are important regulators of protein coding genes. Since the miRNA-mRNA target recognition mechanism is vulnerable to disruption by DNA polymorphisms, we investigated whether polymorphisms in the DISC13′UTR affect binding of miRNAs and lead to allele-specific regulation of DISC1. We identified four predicted polymorphic miRNA target sites in the DISC13′UTR, and demonstrated that miR-135b-5p regulates the level of DISC1mRNA. Moreover, DISC1regulation by miR-135b-5p is allelespecific: miR-135b-5p only binds to the major allele(A) of rs11122396, not to the minor allele(G). Thus, the G allelemay be functionally related to the DISC1-associated phenotypes by abolishing regulation by miR-135b-5p, leading to elevated DISC1levels.