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Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome.
Merico, Daniele; Zarrei, Mehdi; Costain, Gregory; Ogura, Lucas; Alipanahi, Babak; Gazzellone, Matthew J; Butcher, Nancy J; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Chow, Eva W C; Andrade, Danielle M; Frey, Brendan J; Marshall, Christian R; Scherer, Stephen W; Bassett, Anne S.
Afiliación
  • Merico D; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
  • Zarrei M; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
  • Costain G; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Medical Genetics Residency Training Program, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada.
  • Ogura L; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
  • Alipanahi B; Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada.
  • Gazzellone MJ; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
  • Butcher NJ; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
  • Thiruvahindrapuram B; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
  • Nalpathamkalam T; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
  • Chow EW; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada.
  • Andrade DM; Division of Neurology, Department of Medicine, University of Toronto, Ontario, M5S 1A8 Canada, University of Toronto, Toronto, Ontario, Canada Epilepsy Genetics Program, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Ontario, M5T 2S8 Canada.
  • Frey BJ; Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada.
  • Marshall CR; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
  • Scherer SW; The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5G 0A4 Canada.
  • Bassett AS; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Department of Psychiatry University of Toronto, Ontario, M5T 1R8 Canada, University of Toronto, Toronto, Ontario, Canada Department of Psychiatry, and Toronto General Research Institute, University H
G3 (Bethesda) ; 5(11): 2453-61, 2015 Sep 16.
Article en En | MEDLINE | ID: mdl-26384369
Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal P = 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esquizofrenia / Genoma Humano / Síndrome de DiGeorge Tipo de estudio: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Adult / Female / Humans / Male / Middle aged Idioma: En Revista: G3 (Bethesda) Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esquizofrenia / Genoma Humano / Síndrome de DiGeorge Tipo de estudio: Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adolescent / Adult / Female / Humans / Male / Middle aged Idioma: En Revista: G3 (Bethesda) Año: 2015 Tipo del documento: Article Pais de publicación: Reino Unido