Psych Gene (Copy Number Variation and Endophenotypes in Psychiatric Disorders)

This project is supported through the people programme of the European Community‘s FP7, Grant agreement number PIAG-GA-2008-218251

Project overview:

A genome-wide copy number variant (CNV) association study for schizophrenia (SZ), bipolar disorder (BP) and major depression (MD) will be conducted at deCODE genetics using a discovery sample of a total of 2400 individuals (800 SZ, 600 BP, 1,000 MD) and more than 20,000 control individuals. CNV data will be generated from the newly released HumanCNV370 array designed by deCODE genetics and Illumina (www.illumina.com). In this array there are about 55,000 SNPs or univariant probes covering 14,000 segments over the unSNPable genome (gaps in the HapMap project), segmental duplications, megasatellites, and previously discovered CNVs. Algorithms for analyzing these data are being developed at deCODE, and employees from the Research Institute of Biological Psychiatry (RIBP) of Copenhagen University Hospital and Center for Biological Sequence analysis (CBS) at Denmarks Technical University will work with deCODE on analyzing the data and transfer the knowledge to RIBP and CBS. CNVs associating with SZ, BP and MD in Iceland will be tested in SZ (n=800), BP (n=600) and MD (n=600) samples from RIBP using TaqMan probes to measure gene dosage. The confirmation and subsequent functional analysis, including effects of identified CNVs on gene expression, will be carried out at deCODE.

Scientists from both RIBP and CBS will test disease-specific candidate genes, derived from biological networks, for association to the respective disorders in the Icelandic samples, and transfer the knowledge to deCODE. These methods, including the human phenome-interactome1 developed at CBS, will reduce the correction factor for false positive findings, as only a small subset of the polymorphisms (SNPs and CNVs) will be investigated. Thus it will be possible to positively identify susceptibility variants conferring lower risk than otherwise. Associated markers identified by this method, will be genotyped in the RIBP samples using double matched controls of unaffected subjects for confirmation.

Variants, significantly associating with the respective psychiatric disorders in the follow-up samples, will be studied further by analyzing endophenotypes, i.e. treatment response, severity, etc. for the associating CNVs and SNP markers in candidate genes in the RIBPsamples. This will implement data stored in the Danish Psychiatric Biobank maintained at RIBP. Scientists from deCODE will work with scientists from RIBP on analyzing the endophenotypic data. Furthermore samples and phenotypic data from first degree relatives of SZ, BP and MD patients will be collected, analyzed and genotyped for CNVs and SNPs.

Knowledge transfer:

Knowledge transferred from deCODE to RIBP and CBS: 1) Software and algorithms for analysing CNV and conventional SNP data, 2) Genome-wide CNV and SNP data from more than 2000 Icelandic SZ, BP and MD patients and 20,000 controls.

The Research Institute for Biological Psychiatry (RIBP) at Copenhagen University Hospital has a long standing expertise in examining treatment response and other phenotypic features of common psychiatric illnesses such as SZ, BP and MD. RIBP also has big patient samples, with over 2000 affected individuals for the three disorders combined, available for genotyping to follow up findings from the Icelandic discovery sample.

Knowledge transferred from RIBP to deCODE and CBS: 1) Expertise in phenotypic features and biological networks concerning common psychiatric disorders. 2) Extensive phenotype data from more than 2000 SZ, BP and MD patients and double matched controls.

The Center for Biological Sequencing (CBS) at Denmarks Technical University has developed well documented methods to build biological networks by cross-referencing the vast amount of biological data stored in publically available databases. The phenotypic expertise and expertise and knowledge of the neurobiology underlying the disorders under investigation will be transferred to deCODE. The collaboration with RIBP and deCODE allows CBS the opportunity to test their methods on very large data sets, otherwise unavailable to them.

Knowledge transferred from CBS to RIBP and deCODE: Expertise in building biological networks applying data from public databases.