Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies

Arnedo, Javier, Svrakic, Dragan M., del Val, Coral, Romero-Zaliz, Rocio, Hernandez-Cuervo, Helena, Fanous, Ayman H., Pato, Michele T., Pato, Carlos N., de Erausquin, Gabriel A., Cloninger, C. Robert, Zwir, Igor, Molecular Genetics of Schizophrenia Consortium and Mowry, B. J. (2015) Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies. American Journal of Psychiatry, 172 2: 139-153. doi:10.1176/appi.ajp.2014.14040435


Author Arnedo, Javier
Svrakic, Dragan M.
del Val, Coral
Romero-Zaliz, Rocio
Hernandez-Cuervo, Helena
Fanous, Ayman H.
Pato, Michele T.
Pato, Carlos N.
de Erausquin, Gabriel A.
Cloninger, C. Robert
Zwir, Igor
Molecular Genetics of Schizophrenia Consortium
Mowry, B. J.
Title Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies
Journal name American Journal of Psychiatry   Check publisher's open access policy
ISSN 1535-7228
0002-953X
Publication date 2015-02-01
Year available 2015
Sub-type Article (original research)
DOI 10.1176/appi.ajp.2014.14040435
Volume 172
Issue 2
Start page 139
End page 153
Total pages 15
Place of publication Arlington, VA United States
Publisher American Psychiatric Association
Collection year 2016
Language eng
Formatted abstract
Objective:
The authors sought 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 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.

Results:
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%).

Conclusions:
Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
 
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