Interaction of multiple gene variants and their effects on schizophrenia phenotypes

Schizophrenia is a clinically heterogeneous disorder and may be explained by its complex genetic architecture. Many schizophrenia susceptibility genes were identified but the picture remains unclear due to inconsistent or contradictory genetic association studies. This confusion may, in part, be because symptoms result from the combined interaction of many genes and these interacting genes are associated with specific sub-phenotypes of schizophrenia rather than schizophrenia as a whole. This study investigates the relationship between schizophrenia susceptibility genes and schizophrenia sub-phenotypes by identifying multiple gene variant interactions.

Fifty SNPs from 21 genes were genotyped in 235 Australian participants with schizophrenia screened for various phenotypes. Schizophrenia participants were grouped into relevant phenotype clusters using cluster analysis and normalized phenotype cluster scores were calculated for each patient. The relationship between genotypes and normalized phenotype cluster scores were analyzed by linear regression analysis.

Three phenotype clusters were identified. There was some overlap in symptoms between phenotype clusters, particularly for depression. However, cluster 1 appears to be characterized by speech disorder and affective behavior symptoms, cluster 2 has predominantly hallucination symptoms and cluster 3 has mainly delusion symptoms. Interaction of five SNPs was found to have an effect on cluster 1 symptoms; ten SNPs on cluster 2 symptoms; and eight SNPs on cluster 3 symptoms.

The interaction of specific susceptibility genes is likely to lead to specific clinical sub-phenotypes of schizophrenia. Larger patient cohorts with more extensive clinical data will improve the detection of gene interactions and the resultant schizophrenia clinical phenotypes.