Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt?

Schizophrenia (SZ) and bipolar disorder (BPD) have high heritabilities and are clinically and genetically complex. Genome wide association studies (GWAS) and studies of copy number variations (CNV) in SZ and BPD have allowed probing of their underlying genetic risks. In this systematic review, we assess extant genetic signals from published GWAS and CNV studies of SZ and BPD up till March 2011. Risk genes associated with SZ at genome wide significance level (p value<7.2 × 10(-8)) include zinc finger binding protein 804A (ZNF804A), major histocompatibility (MHC) region on chromosome 6, neurogranin (NRGN) and transcription factor 4 (TCF4). Risk genes associated with BPD include ankyrin 3, node of Ranvier (ANK3), calcium channel, voltage dependent, L type, alpha 1C subunit (CACNA1C), diacylglycerol kinase eta (DGKH), gene locus on chromosome 16p12, and polybromo-1 (PBRM1) and very recently neurocan gene (NCAN). Possible common genes underlying psychosis include ZNF804A, CACNA1C, NRGN and PBRM1. The CNV studies suggest that whilst CNVs are found in both SZ and BPD, the large deletions and duplications are more likely found in SZ rather than BPD. The validation of any genetic signal is likely confounded by genetic and phenotypic heterogeneities which are influenced by epistatic, epigenetic and gene-environment interactions. There is a pressing need to better integrate the multiple research platforms including systems biology computational models, genomics, cross disorder phenotyping studies, transcriptomics, proteomics, metabolomics, neuroimaging and clinical correlations in order to get us closer to a more enlightened understanding of the genetic and biological basis underlying these potentially crippling conditions.