Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?

Abstract

Large-scale genomic studies of schizophrenia have identified hundreds of genetic loci conferring risk to the disorder. This progress offers an important route toward defining the biological basis of the condition and potentially developing new treatments. In this review, we discuss insights from recent genome-wide association study, copy number variant, and exome sequencing analyses of schizophrenia, together with functional genomics data from the pre- and postnatal brain, in relation to synaptic development and function. These data provide strong support for the view that synaptic dysfunction within glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurons of the cerebral cortex, hippocampus, and other limbic structures is a central component of schizophrenia pathophysiology. Implicated genes and functional genomic data suggest that disturbances in synaptic connectivity associated with susceptibility to schizophrenia begin in utero but continue throughout development, with some alleles conferring risk to the disorder through direct effects on synaptic function in adulthood. This model implies that novel interventions for schizophrenia could include broad preventive approaches aimed at enhancing synaptic health during development as well as more targeted treatments aimed at correcting synaptic function in affected adults.

Keywords: Genetics; Genomics; Neurodevelopment; Schizophrenia; Synapse; Synaptic plasticity.

Figure 1

Estimated odds ratios for DNA variants at example synaptic gene loci associated with schizophrenia and their observed frequency in schizophrenia cases in the corresponding studies. Damaging variants (blue dots) encompass rare protein-truncating variants and missense (nonsynonymous) coding variants with an MPC (missense badness, polyphen-2, constraint) pathogenicity score >3, as identified in the recent exome sequencing study of the Schizophrenia Exome Meta-Analysis (SCHEMA) Consortium (17). Estimated schizophrenia odds ratio and population frequency of NRXN1 deletions (black dot) are calculated from the copy number variant meta-analysis of Marshall et al. (20). Estimated schizophrenia odds ratios and population frequencies of common (>1% population frequency) DNA variants (green dots) are derived from the recent genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium (16).

Figure 2

Developmental timing of synaptic processes in the human frontal cortex of potential relevance to schizophrenia (40, 41, 42,94). Examples of genes implicated in schizophrenia susceptibility that have been reported to serve a role in these processes are provided (references in superscript). Genes in blue font are implicated in schizophrenia risk through exome sequencing (17); genes in green font are implicated through fine-mapping of genome-wide association study risk loci (16); NRXN1 is implicated through copy number variation disrupting this gene (20). Note that individual genes can be in involved in multiple synaptic and other biological processes.