Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders

• Published in: Molecular psychiatry Vol. 19; no. 8; pp. 872 - 879
• Main Authors: KENNY, E. M, CORMICAN, P, CORVIN, A. P, DONOHOE, G, GALLAGHER, L, GILL, M, MORRIS, D. W, FURLONG, S, HERON, E, KENNY, G, FAHEY, C, KELLEHER, E, ENNIS, S, TROPEA, D, ANNEY, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.08.2014
• Subjects: Adult and adolescent clinical studies; Amino acid sequence; Autism; Biological and medical sciences; Case-Control Studies; Cell adhesion molecules; Child clinical studies; Child Development Disorders, Pervasive - genetics; Developmental disorders; Disc1 protein; European Continental Ancestry Group - genetics; Female; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic research; Genetic susceptibility; Glutamic acid receptors; Health aspects; Humans; Infantile autism; Male; Medical sciences; Mental disorders; Middle Aged; Molecular modelling; Mutation - genetics; Nerve Tissue Proteins - genetics; Neural coding; Neurodevelopmental disorders; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Risk factors; Schizophrenia; Schizophrenia - genetics; Synapses; Synaptogenesis; loss-of-function; Schizophrenia; Developmental disorder; Genetic determinism; Autism spectrum disorder; sequencing; Psychosis; Autism; Synapse; Pervasive developmental disorder; Gene; Genetics; Mutation
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2013.127

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.