Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies

Abstract

Objective: To demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes. Method: In a large genome-wide association study (GWAS) of cases with schizophrenia and controls, we first identified sets of interacting singlenucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of clinical status. Second, we examined the risk of schizophrenia for each SNP set, and tested replicability in two independent samples. Third, we identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, we identified sets of distinct clinical features that cluster in particular cases (i.e., phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, we tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies. Results: We identified 42 SNP sets associated with 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. 17 networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the Schizophrenias)5 varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%). Conclusions: Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.