THE DISC1 GENE AND MAJOR MENTAL ILLNESS IN FINLAND

Background Linkage and association studies of major mental illness in Finland have continually identified the 1q42 region, and the Disrupted in Schizophrenia 1 (DISC1) gene in particular, as being a key locus of interest. Haplotypes and variants in the DISC1 gene have been associated with Schizophrenia (SCZ), bipolar disorder, and autism spectrum disorders, as well as to variations in related endophenotypes such as visual working memory, anhedonia, and gray matter volume in the dorsal lateral prefrontal cortex. Despite this consistent line of evidence for these loci in the Finnish population, any true causal variants within the DISC1 gene are yet to be identified. Methods To identify any potential mutations, a subset of families ascertained for SCZ (n=20 families, 96 individuals) were sequenced using Nimblegen SeqCap EZ for the DISC1 gene locus, including TSNAX. All identified variants were then prioritized using association analysis (p Results With the aid of this three-step sequencing and genotyping approach, we identified 1,828 variants in the DISC1 gene, of which 28 variants were identified as associated (p Discussion We aim to identify the potential mutations within the DISC1 gene which have been alluded to through our previous studies of Finnish cohorts for major mental illness. Our initial findings confirm the observation of association for several variants in the DISC1 gene for varied phenotypes, while focusing on the specific variants that have potential functional consequences. The variants we report may represent the principal major mental illness mutations within the DISC1 gene in the Finnish population. Once the relevance of these mutations to multiple diagnostic criteria is determined, we will study these mutations with respect to alternative phenotypes to the diagnoses available in these cohorts, including neuropsychological endophenotypes, neuroimaging, gene expression levels from lymphocytes, and medication usage.