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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

Authors

Maria Koromina

Miles Flitton

Alix Blockley

IAN MELLOR ian.mellor@nottingham.ac.uk
Assistant Professor



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, 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
Journal Scientific Reports
Print ISSN 2045-2322
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

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