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

VILLAR, MARÍA JOSÉ; GASPAR, PABLO A.; SILVA, HERNÁN; MATURANA, ALEJANDRO; HERRERA, LUISA; SALINAS, VALERIA; NIETO, RODRIGO; BUSTAMANTE, M. LEONOR

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2017 vol. 174 p. 663 - 670

1552-4841

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.