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

The authors sought to demonstrate that schizophrenia is a
heterogeneous group of heritable disorders caused by different genotypic
networks that cause distinct clinical syndromes.

In a large genome-wide association study of cases with
schizophrenia and controls, the authors first identified sets of
interacting single-nucleotide polymorphisms (SNPs) that cluster within
particular individuals (SNP sets) regardless of clinical status. Second,
they examined the risk of schizophrenia for each SNP set and tested
replicability in two independent samples. Third, they identified
genotypic networks composed of SNP sets sharing SNPs or subjects.
Fourth, they identified sets of distinct clinical features that cluster
in particular cases (phenotypic sets or clinical syndromes) without
regard for their genetic background. Fifth, they tested whether SNP sets
were associated with distinct phenotypic sets in a replicable manner
across the three studies.

The authors identified 42 SNP sets associated with a 70% or
greater risk of schizophrenia, and confirmed 34 (81%) or more with
similar high risk of schizophrenia in two independent samples. Seventeen
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) 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%).

Schizophrenia is a group of heritable disorders caused by a
moderate number of separate genotypic networks associated with several
distinct clinical syndromes.

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