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Schizophrenia Subtypes Identified By Combining Genetic, Clinical Data

NEW YORK (GenomeWeb) – Schizophrenia encompasses several distinct subtypes, each characterized by different symptoms and genetic variant clusters, according to a new study.

As they reported in the American Journal of Psychiatry, members of a Washington University-led team that included representatives from the Molecular Genetics of Schizophrenia Consortium brought together genome-wide SNP profiles for thousands of individuals with or without schizophrenia to start defining sets of risk variants that co-occur.

After verifying dozens of these SNP clusters in still other study cohorts, the team folded in clinical information to find eight sets of risk variants that consistently coincided with the presence or lack of certain schizophrenia symptoms and seemed to represent new schizophrenia classes or subtypes.

"Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes," the study's authors wrote, noting that these findings hint at the possibility of refining the way schizophrenia is diagnosed and treated in the future.

Past studies suggest that many risk variants contribute to schizophrenia, though it has been difficult to define the complete suite of genetic interactions that can produce the highly heritable condition. For their part, the study's authors speculated that "schizophrenia heritability is not missing but is distributed into different networks of interacting genes that influence different people."

"[Genes] function in concert much like an orchestra, and to understand how they're working, you have to know not just who the members of the orchestra are but how they interact," Washington University psychiatry and genetics researcher Robert Cloninger, a senior author on the study, said in a statement.

In an effort to define risk gene networks for schizophrenia — and potentially link them to phenotypic features found in those with the disease — he and his colleagues started by scrutinizing genotype profiles for 4,196 schizophrenic individuals with known phenotypic features enrolled through the Molecular Genetics of Schizophrenia project.

When they compared those SNP patterns to the genotypes present in 3,827 unaffected controls, the researchers narrowed in on hundreds of variants that appeared to be over-represented in individuals with schizophrenia.

A closer look at those variants revealed 42 SNPs clusters that were present in one or more individuals. Generally speaking, the team found that larger groups of variants tended to turn up in fewer and fewer schizophrenia cases and vice versa.

One trio of shared risk SNPs turned up in more than 250 individuals with schizophrenia, for instance, while a larger set of two-dozen schizophrenia-associated variants fell in 70 cases.

For their follow-up analyses, the researchers not only considered the level of schizophrenia risk associated with each SNP cluster but also the shared clinical features found in individuals carrying similar variant sets.

In the process, the team defined eight schizophrenia subtypes that were subsequently replicated in more than 1,000 additional cases enrolled through the Clinical Antipsychotic Trial of Intervention Effectiveness and the Psychiatric Genomics Consortium projects.

These sub-groups included individuals with varying types of symptoms and severity — from auditory or other hallucinations to disorganized speech and behavior — which were linked to SNP sets associated with schizophrenia risk to varying degrees.

"[W]e were able to find that different sets of genetic variations were leading to distinct clinical syndromes," Cloninger said. "So I think this really could change the way people approach understanding the causes of complex diseases."

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