(Visual) Endophenotypes in schizophrenia research

Objective: Schizophrenia is a heterogeneous disease strongly influenced by genetic disposition. However, genetic studies have shown that each single nucleotide polymorphism (SNP) contributes very little to the disease. For this reason, endophenotypes, located in between the genetic and clinical level, have become of great interest. Due to its heterogeneity, schizophrenia is likely not caused by one abnormality. Here, we asked the question to what extent deficits in various endophenotypes tap into the same deficits of schizophrenia. Methods: We tested schizophrenia patients, their relatives, and controls with a battery of perceptual and cognitive tests, such as visual backward masking, out of body experience, the Wisconsin Card Sorting Test (WCST), verbal fluency, and the continous performance task (CPT). Results: First, we found that visual backward masking is an extremely sensitive endophenotype of schizophrenia. Deficits are specific to the psychosis spectrum and not evident in depressive patients and abstinent alcoholics. As expected from an endophenotype, not only the patients but also their siblings show clear performance deficits, as well as adolescents with psychosis. Both genetic analysis and EEG recordings point to deficiencies in the cholinergic system. We then compared performance in visual backward masking with other tests. Surprisingly, performance in most tests did not correlate with each other. Conclusions: Our results suggest that each endophenotype is sensitive to different abnormal mechanisms. Schizophrenia is much more complex than previously thought. Heterogeneity can be best attacked by the combined investigation of sensitive endophenotypes.