The MIR137 region in schizophrenia: genomics, variant discovery & association

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DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is an often devastating neuropsychiatric illness with a lifetime prevalence of 0.4%. The current understanding of the polygenic nature of this disease underscores the complexity of understanding SCZ etiology. New and exciting novel findings from the Psychiatric GWAS Consortium (PGC) have identified significant and replicated association for a region on chromosome 1 near MIR137. Meta-analysis of the published PGC GWAS data with a Swedish sample (N=21,856) yielded a top significant SNP of p=1.7X10-9, located approximately 40kb upsteam of the region encoding the MIR137 stem-loop sequence. MIR137 has also been functionally implicated through identification of significant genome wide association for four genes which have confirmed miR-137 target sites (CACNA1C, TCF4, CSMD1, and C10orf26). Analysis of the PGC- GWAS data also shows that predicted miR-137 targets were enriched for association compared with genes matched for size and marker density (p<0.01). These findings suggest that there exists a variant in this region, likely affecting miR-137 function that alters risk for SCZ. However, to date, no functional variants have been reported and linked to SCZ risk. We therefore propose a set of experiments designed to identify both novel and known variants that are the best candidates for functionally affecting either MIR137 or other genes, thereby directly contributing to SCZ risk. This work involves: 1) verification of transcriptional and genomic architecture through novel and innovative techniques, including sequencing of nascent RNA (GRO-seq) and long-read sequencing of select individuals; 2) sequencing SCZ cases and controls for identification of novel variants 3) functional annotation using existing databases and data from our work on the region and 4) genotyping of a large case control dataset to determine which variants are associated with SCZ. This will yield highly detailed and prioritized list of variants that are likey to contribute to risk of SCZ in the population. This will provide for the basis of future grant applications molecularly confirming the functional effect of variants on nearby genes and in the SCZ population. This region provides the best opportunity yet to identify pieces to the complex puzzle of SCZ etiology.