Evidence for the Association between the Intronic Haplotypes of Ionotropic Glutamate Receptors and First-Episode Schizophrenia

Abstract

The heritable component of schizophrenia (SCH) as a polygenic trait is represented by numerous variants from a heterogeneous group of genes each contributing a relatively small effect. Various SNPs have already been found and analyzed in genes encoding the NMDAR subunits. However, less is known about genetic variations of genes encoding the AMPA and kainate receptor subunits. We analyzed sixteen iGluR genes in full length to determine the sequence variability of iGluR genes. Our aim was to describe the rate of genetic variability, its distribution, and the co-occurrence of variants and to identify new candidate risk variants or haplotypes. The cumulative effect of genetic risk was then estimated using a simple scoring model. GRIN2A-B, GRIN3A-B, and GRIK4 genes showed significantly increased genetic variation in SCH patients. The fixation index statistic revealed eight intronic haplotypes and an additional four intronic SNPs within the sequences of iGluR genes associated with SCH (p < 0.05). The haplotypes were used in the proposed simple scoring model and moreover as a test for genetic predisposition to schizophrenia. The positive likelihood ratio for the scoring model test reached 7.11. We also observed 41 protein-altering variants (38 missense variants, four frameshifts, and one nonsense variant) that were not significantly associated with SCH. Our data suggest that some intronic regulatory regions of iGluR genes and their common variability are among the components from which the genetic predisposition to SCH is composed.

Study on the causal relationship between educational attainment and delirium: A two-sample Mendelian randomization study

“…The incidence of delirium is estimated to be approximately 20%–50%, and the incidence of delirium in critically ill patients receiving mechanical ventilation is as high as 60%–80% [ 1 ]. The pathogenesis of delirium is mainly associated with genetic and risk factors, and it is currently believed to be associated with the apolipoprotein E4 (ApoE4) allele [ 3 ], dopamine [ 4 ]and N-methyl-D-aspartate (NMDA) receptor genes [ 5 ]. On the other hand, delirium-related risk factors have a non-negligible influence on the development of delirium, and common risk factors include age, smoking, surgery, infection, and history of previous use of certain drugs [ 6 ].…”