Despite these caveats, there is good reason for optimism that the association with schizophrenia is real. First, the statistical support is becoming more compelling in that increasing GWAS sample sizes have been associated with ever decreasing p values that make the probability of a type I error vanishingly small. Furthermore, a new Irish sample independent of the most recent Psychiatric Genomics Consortium meta-analysis supported the MHC association and, by imputation, found that the most significant result was with a classic HLA-C marker, a class I MHC molecule (16). Second, several strands of research suggest that the MHC plays an important role in neuronal function, with expression levels affecting synaptic plasticity and potentially the formation of new memories (17). Specifically, there is now evidence that class I MHC proteins regulate synaptic responses mediated by N-methyl-d-aspartic acid (NMDA) type glutamate receptors (NMDARs) in the mammalian CNS. The mechanism appears to work via tonic inhibition of NMDAR function, which in turn affects downstream NMDAR-induced AMPA receptor trafficking (18). Recent data also indicate that not only are MHC class I proteins required for normal postnatal brain development and plasticity, but they are also widely expressed in the mammalian brain prenatally during the earliest stages of neuronal differentiation (19), consistent with a possible role in neurodevelopmental disorders. Finally, the study by Walters et al. in this issue (2), which looks at structural MRI and cognitive measures in patients with schizophrenia and healthy comparison subjects, found significant associations between a SNP in the MHC, previously identified by schizophrenia GWAS, and both delayed episodic memory and decreased hippocampal volume.