@misc{10481/101115,
year = {2014},
month = {10},
url = {https://hdl.handle.net/10481/101115},
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.},
organization = {Supported in part by the Spanish Ministry of Science and Technology (projects TIN2009-13950 and TIN2012-38805) and by the R.L. Kirschstein National Research Award to Dr. Zwir; by NIH for the Molecular Genetics of Schizophrenia Consortium, including NIH grants R01MH060879, R01MH067257, R01MH059588, R01MH059571, R01MH059565, R01MH059587, R01MH060870, R01MH059566, R01MH059586, R01MH061675, R01MH081800, U01MH046276, U01MH046289, U01MH046318, U01MH079469, U01MH079470, 5K08MH077220, 5R01MH052618-05, 5R01MH058693-06, and 3R01MH085548-05S1; and by the Genetic Association Information Network.},
keywords = {Schizophrenia},
keywords = {SNP},
keywords = {GWAS},
keywords = {Risk Architecture},
title = {Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies},
doi = {10.1176/appi.ajp.2014.14040435},
author = {Arnedo Fernández, Francisco Javier and Svrakic, Dragan and Val Muñoz, María Coral Del and Romero Zaliz, Rocio Celeste and Hernández-Cuervo, Helena and Molecular Genetics of Schizophrenia Consortium and Fanous, Ayman and Pato, Michele and Pato, Carlos and de Erausquin, Gabriel and Cloninger, Robert and Zwir Nawrocki, Jorge Sergio Igor},
}