title: Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome.
abstract: 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.
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Zarrei
authors.affiliation: 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.
authors.forename: Gregory
authors.initials: G
authors.lastname: Costain
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ogura
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada.
authors.forename: Babak
authors.initials: B
authors.lastname: Alipanahi
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gazzellone
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Butcher
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapuram
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nalpathamkalam
authors.affiliation: 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.
authors.forename: Eva W C
authors.initials: EW
authors.lastname: Chow
authors.affiliation: 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.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Andrade
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4 Canada, University of Toronto, Toronto, Ontario Canada.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4 Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: 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.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: 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 Health Network, Toronto, Ontario, Canada Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5S 2S1 Canada The Dalglish Family Hearts and Minds Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto, Ontario, M5G 2C4 Canada anne.bassett@utoronto.ca.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D004062:DiGeorge Syndrome / Q000150:complications* / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D062085:RNA, Long Noncoding / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*
chemical_list: C474043:DGCR8 protein, human; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins
keywords: 22q11 deletion syndrome; ABLIM1; BSN; DGCR8; DIP2A; EXOC4; FMR1; ITM2C; MYH10; MYH9; PCNT; PTPRG; SLITRK2; ZDHHC5; connectivity; copy number variation; genetic architecture; lincRNA; microRNA; next-generation sequencing; noncoding RNA; polygenic risk score; postsynaptic density; schizophrenia; synapse