Genome wide association study in schizophrenia and intermediate phenotypes

Schizophrenia is a devastating brain disease with high heritability: A major challenge in medicine is to understand mechanisms underlying severe mental diseases including schizophrenia, affecting 0,5–1% of the population. It mostly presents with several episodes and tends to become chronic. Ca. 30% of patients require support throughout their lives. The mode of inheritance is complex and non-Mendelian with a high heritability of ca. 80%. There is a long lasting assumption in psychiatric genetics that common genetic variants with small effects are enhancing the risk to develop e.g. schizophrenia. Although debated for some time, the other side of the coin namely that rare genetic variations with large effects may account for a significant number of schizophrenia cases has been somehow neglected. Rare structural genomic variants confer high risk for schizophrenia: CNVs are emerging as an important genomic cause of neuropsychiatric diseases, including mental retardation, autism and more recently schizophrenia. We identified specific microdeletions (at 1q21.1, 15q11.2 and 15q13.3) associated with schizophrenia in over 4700 schizophrenia cases and 40000 controls within the SGENE+ consortium. Furthermore, we examined NRXN1 for CNVs in 2977 schizophrenia patients and 33746 controls and found CNVs disrupting exons to be associated. All these findings could represent a decisive step towards understanding the causes of this severe mental disorder as well as developing new potential treatments. Additionally, we use complementary strategies to approach the pathobiology and genetics of schizophrenia including genetic association studies, animal and cell culture models as well as schizophrenia-related intermediate phenotypes. New results of our ongoing genome-wide association studies will be presented and discussed in the light of meta-analyses.