title: De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample.
abstract: 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.
authors.affiliation: Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY 10016, USA.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Kranz
authors.affiliation: Institut Pasteur, Department of Neuroscience, Paris, France.
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
authors.affiliation: Braun School of Public Health and Community Medicine of the Hebrew University-Hadassah Medical Organization in Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Manor
authors.affiliation: Department of Psychiatry, Hebrew University of Jerusalem, Israel.
authors.forename: Pesach
authors.initials: P
authors.lastname: Lichtenberg
authors.affiliation: Genetic Epidemiology, Hebrew University of Jerusalem, Israel.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Friedlander
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Seandel
authors.affiliation: American Foundation for Suicide Prevention, 120 Wall Street, 29th Floor, New York, NY 10005, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Harkavy-Friedman
authors.affiliation: Department of Psychiatry, Social and Psychiatric Initiatives, New York University, 1 Park Avenue, 8th Floor Room 222, New York, NY 10016, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Walsh-Messinger
authors.affiliation: Genome Technology Center, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.affiliation: Genome Technology Center, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, New York, NY 10016, USA.
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.affiliation: 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.
authors.forename: Dolores
authors.initials: D
authors.lastname: Malaspina
mesh_terms: D000328:Adult; D066264:Datasets as Topic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007557:Israel; D008297:Male; D009154:Mutation; D009518:New York; D010290:Parents; D011618:Psychotic Disorders / Q000208:ethnology / Q000235:genetics; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: De novo; Exome sequencing; PTPRG: rare variant; Paternal age; Schizophrenia