A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder

Abstract

Suicidal behavior has been shown to have a heritable component that is partly driven by psychiatric disorders [Brent and Mann, 2005]. However, there is also an independent factor contributing to the heritability of suicidal behavior. We previously conducted a genome-wide association study (GWAS) of bipolar suicide attempters and bipolar non-attempters to assess this independent factor [Willour et al., 2012]. This GWAS implicated glutamatergic neurotransmission in attempted suicide. In the current study, we have conducted a targeted next-generation sequencing study of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, neurexin, and neuroligin gene families in 476 bipolar suicide attempters and 473 bipolar non-attempters. The goal of this study was to gather sequence information from coding and regulatory regions of these glutamatergic genes to identify variants associated with attempted suicide. We identified 186 coding variants and 4,298 regulatory variants predicted to be functional in these genes. No individual variants were overrepresented in cases or controls to a degree that was statistically significant after correction for multiple testing. Additionally, none of the gene-level results were statistically significant following correction. While this study provides no direct support for a role of the examined glutamatergic candidate genes, further sequencing in expanded gene sets and datasets will be required to ultimately determine whether genetic variation in glutamatergic signaling influences suicidal behavior. © 2016 Wiley Periodicals, Inc.

Keywords: GRIN3A; NLGN1; bipolar disorder; candidate gene sequencing; suicidal behavior.

Figure 1

Effect of drug treatments on glutamatergic signaling. Both chronic lithium treatment and acute ketamine treatment inhibit NMDA receptors (shown in purple). These NMDA receptors interact with postsynaptic NLGN proteins (shown in green) through scaffolding protein complexes. These NLGN proteins interact with presynaptic NRXN proteins (shown in blue) to stabilize the synapse and determine synapse specificity.