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

Details

• Alternative Title:
  Schizophr Res
• Personal Author:
  Kranz, Thorsten M ; Harroch, Sheila ; Manor, Orly ; Lichtenberg, Pesach ; Friedlander, Yechiel ; Seandel, Marco ; Harkavy-Friedman, Jill ; Walsh-Messinger, Julie ; Dolgalev, Igor ; Heguy, Adriana ; Chao, Moses V ; Malaspina, Dolores
• Description:
  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.
• Subjects:
  Adult Article Datasets As Topic De Novo Exome Sequencing Female Genetic Predisposition To Disease Humans Israel Male Mutation New York Parents Paternal Age Psychotic Disorders PTPRG: Rare Variant Receptor-Like Protein Tyrosine Phosphatases, Class 5 Schizophrenia Sequence Analysis, DNA

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• Source:
  Schizophr Res. 2015; 166(0):119-124
• Pubmed ID:
  26091878
• Pubmed Central ID:
  PMC4512856
• Document Type:
  Journal Article
• Funding:
  UL1 TR001445/TR/NCATS NIH HHSUnited States/ ; P30 CA016087/CA/NCI NIH HHSUnited States/ ; MH086651/MH/NIMH NIH HHSUnited States/ ; RC1 MH088843/MH/NIMH NIH HHSUnited States/ ; 1DP2HD080352-01/DP/NCCDPHP CDC HHSUnited States/ ; R01 MH059114/MH/NIMH NIH HHSUnited States/ ; UL1TR000038/TR/NCATS NIH HHSUnited States/ ; RC1-MH088843/MH/NIMH NIH HHSUnited States/ ; 5K24MH001699/MH/NIMH NIH HHSUnited States/ ; R01-MH59114/MH/NIMH NIH HHSUnited States/ ; R01 MH086651/MH/NIMH NIH HHSUnited States/ ; K24 MH001699/MH/NIMH NIH HHSUnited States/ ; UL1 TR000038/TR/NCATS NIH HHSUnited States/ ; R56 NS021072/NS/NINDS NIH HHSUnited States/
• Volume:
  166
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:84665238602ecffc5572edccb4de21c1cb70b7611a91af33212b6417b7c05769
• Download URL:
  https://stacks.cdc.gov/view/cdc/34565/cdc_34565_DS1.pdf
• File Type:
  [PDF - 222.08 KB ]