De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample.

Autor: Kranz TM; Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY 10016, USA., Harroch S; Institut Pasteur, Department of Neuroscience, Paris, France., Manor O; Braun School of Public Health and Community Medicine of the Hebrew University-Hadassah Medical Organization in Jerusalem, Israel., Lichtenberg P; Department of Psychiatry, Hebrew University of Jerusalem, Israel., Friedlander Y; Genetic Epidemiology, Hebrew University of Jerusalem, Israel., Seandel M; Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA., Harkavy-Friedman J; American Foundation for Suicide Prevention, 120 Wall Street, 29th Floor, New York, NY 10005, USA., Walsh-Messinger J; Department of Psychiatry, Social and Psychiatric Initiatives, New York University, 1 Park Avenue, 8th Floor Room 222, New York, NY 10016, USA., Dolgalev I; Genome Technology Center, New York University Langone Medical Center, New York, NY 10016, USA., Heguy A; Genome Technology Center, New York University Langone Medical Center, New York, NY 10016, USA., Chao MV; Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY 10016, USA., Malaspina D; Department of Psychiatry, Social and Psychiatric Initiatives, New York University, 1 Park Avenue, 8th Floor Room 222, New York, NY 10016, USA; Creedmoor Psychiatric Center, New York State Office of Mental Health, 79-25 Winchester Boulevard, Queens Village, NY 11427, USA. Electronic address: dolores.malaspina@nyumc.org.
Jazyk: angličtina
Zdroj: Schizophrenia research [Schizophr Res] 2015 Aug; Vol. 166 (1-3), pp. 119-24. Date of Electronic Publication: 2015 Jun 16.
DOI: 10.1016/j.schres.2015.05.042
Abstrakt: Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.
(Copyright © 2015 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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