title: Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.
abstract: Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: E M
authors.initials: EM
authors.lastname: Kenny
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Cormican
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Furlong
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Heron
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Kenny
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Fahey
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Kelleher
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: Tropea
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: R
authors.initials: R
authors.lastname: Anney
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: A P
authors.initials: AP
authors.lastname: Corvin
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Donohoe
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: D W
authors.initials: DW
authors.lastname: Morris
mesh_terms: D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins