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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.

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Acknowledgements

We sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. Funding for this study was provided by the Health Research Board (HRB Ireland; HRA/2009/45) and Science Foundation Ireland (SFI; 08/IN.1/B1916). Next-generation sequencing was performed in TrinSeq (Trinity Genome Sequencing Laboratory; http://www.medicine.tcd.ie/sequencing), a core facility funded by SFI under Grant No. [07/RFP/GEN/F327/EC07] to Dr Morris. Ms Furlong’s PhD studentship is funded by the HRB 4-Year PhD Programme in Molecular Medicine at TCD. We acknowledge use of the Trinity Biobank control sample and support from the Trinity Centre for High Performance Computing. This work was supported by grant funding from the Health Research Board (Ireland).

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Kenny, E., Cormican, P., Furlong, S. et al. Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol Psychiatry 19, 872–879 (2014). https://doi.org/10.1038/mp.2013.127

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  • DOI: https://doi.org/10.1038/mp.2013.127

Keywords

  • autism
  • loss-of-function
  • mutation
  • schizophrenia
  • sequencing
  • synapse

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