55 - LARGE META-ANALYSIS OF SCANDINAVIAN EXOME SEQUENCING STUDIES OF SCHIZOPHRENIA

Abstract

Background The current data indicated that the allelic architecture of complex traits is caused by many common and rare variants. Large GWAS meta-analyses have been successfully applied in the search for common variants affecting the risk of developing psychiatric disorders, in particular schizophrenia and Major Depressive Disorder. However, these studies are designed to examine only the common variant proportion of the genomic landscape whereas high-throughput sequencing allows direct examination of both common and rare alleles. Schizophrenia is one of the most disabling mental disorders; it has a lifetime prevalence of around 1% and a heritability estimated as high as 80%. Although around one third of the heritability can be attributed to common variants, prior studies indicate that rare variants also contribute to its etiology. Methods A collaboration between iPSYCH (The Lundbeck Initiative for Integrative Psychiatric Research, Denmark) and the Broad Institute (in Cambridge, MA, USA) is conducting large scale exome sequencing of major psychiatric disorders, including schizophrenia. DNA is extracted from dried blood spots (DBS) stored at the Danish Neonatal Screening Biobank. The samples can be matched to a wide range of phenotypic information available in Danish registries. Results We present here the analysis of a large collection of schizophrenia individuals recruited in clinical centers (1,866) and from DBS samples (3,710): a total of 5,576 cases and 7,468 controls from Denmark. We follow up in a similarly sized sample from Sweden with 4,969 cases and 6,245 controls. The combined analysis represents the largest exome sequencing study in schizophrenia to date. We have found evidence showing a higher per-person rate of disruptive ultra-rare loss-of-function variants located in constrained genes among schizophrenia cases compared to controls (combined p-value 1.6e-07). Meta-analysis SKAT of rare and ultra-rare variants at gene level has been performed. Discussion The results from burden and enrichment analysis, as well as ranking of mutational load, will be discussed in the larger perspective of findings from both GWAS and other exome analyses in schizophrenia.