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Am J Med Genet B Neuropsychiatr Genet. 2017 Oct;174(7):663-670. doi: 10.1002/ajmg.b.32550. Epub 2017 Jun 14.

Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype.

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Faculty of Medicine, Program of Human Genetics, Biomedical Sciences Institute, Universidad de Chile, Santiago de Chile, Chile.
Clínica Psiquiátrica Universitaria, Universidad de Chile, Santiago de Chile, Chile.
Faculty of Medicine, Department of Neurosciences, Universidad de Chile, Santiago de Chile, Chile.
Biomedical Neurosciences Institute, Universidad de Chile, Santiago de Chile, Chile.


Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants.


cognitive disturbances; genetic epidemiology; psychosis

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