Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

Koromina, Maria; Flitton, Miles; Blockley, Alix; Mellor, Ian R; Knight, Helen

Abstract

Schizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 x 10-10), and identified a significant burden of functional variants for Scz (p < 1.6 x 10-11) and ASD (p = 6.9 x 10-18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 x 10-15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease

Citation

Koromina, M., Flitton, M., Blockley, A., Mellor, I. R., & Knight, H. (2019). Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities. Scientific Reports, 9, Article 19215. https://doi.org/10.1038/s41598-019-55635-4

• Journal Article Type: Article
• Acceptance Date: Nov 23, 2019
• Online Publication Date: Dec 16, 2019
• Publication Date: Dec 16, 2019
• Deposit Date: Dec 4, 2019
• Publicly Available Date: Dec 17, 2019
• Journal: Scientific Reports
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 19215
• DOI: https://doi.org/10.1038/s41598-019-55635-4
• Public URL: https://nottingham-repository.worktribe.com/output/3462227
• Publisher URL: https://www.nature.com/articles/s41598-019-55635-4