Genome wide study of Italian schizophrenia patients

Schizophrenia (SZ) is a common psychiatric disorder with an estimated heritability up to 80%. Despite its high and clear heritability, its genetic architecture is less clear and more contentious. After 20 years of molecular genetics researches, new molecular strategies, primary based on microarray, have revealed that the "Common Variant, Common Disease" model is not suitable to explain the genetics of SZ, which instead would be better explained by a mixed model including the contribution of multiple rare high penetrant risk variants combined with regulatory common variants. Although many copy number variations (CNVs) are now considered confirmed SZ risk factors, a considerable amount of heritability still remains to be explained. On the light of these observations we performed a genome wide scan with the Affymetrix 6.0 SNP array on a cohort of 180 SZ patients and 171 healthy controls to better understand the contribution of common and rare variants in the etiopathogenesis of SZ in the Italian population. From this study, we identified some CNVs already convincingly implicated as risk factors for schizophrenia as well as new, rare, large CNVs potentially associated to the clinical phenotype. Moreover, an increased frequency of runs of homozigosity was observed among SZ subjects, as a result of a high level of inbreeding of 6 patients whose clinical phenotype could be due to the presence of deleterious homozygous functional variants. Finally, the result of the GWAS, suggested the involvement of the C20orf39 gene as risk factor for SZ. In conclusion, if we consider that the estimated hereditability for SZ is between 0.5-0.8 and that in at least 12 patients the clinical phenotype could be due to the presence of a CNV and in 6 patients to the presence of recessive variants, we could hypothesize that rare variants detectable by SNP array platform account for approximately 13-21% of the genetic variability of our cohort of SZ patients.