Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder

Abstract

Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 × 10−4). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD.

Sex differences in glutamate receptor gene expression in major depression and suicide

“…[17][18][19][20][21][22] In addition to genetic variation, environmental factors such as early life adversity can influence gene expression. 23 Gene expression is a reflection of both genetic (inherited) and environmental precipitants of MDD.…”

Specific and common genes implicated across major mental disorders: A review of meta-analysis studies

“…Of these studies, 4 focused on MDD (Lee et al, 2012;Lewis et al, 2010;Shyn et al, 2011;Wray et al, 2012), 3 on SZ (Jia et al, 2012;Shi et al, 2009;Wang et al, 2012), 2 on ADHD (Ebejer et al, 2013;Neale et al, 2010), 1 on BD (Goes et al, 2012) and 1 on AD (Otowa et al, 2012). We also identified one other study that conducted a meta-analysis across GWAS data of SZ and BD patients combined (Wang et al, 2010).…”

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

“…Studies of common variants, rare mutations, and structural variations have also documented genetic overlap among a range of psychiatric disorders (Smoller, 2013). Beyond the growing catalog of established risk variants, pathway analyses have begun to implicate functional sets of genes in multiple disorders, including genes involved in immune function, glial cell function, calcium channel signaling, glutamatergic neurotransmission, histone methylation, structural elements of the postsynaptic density, and targets of the fragile X mental retardation protein (FMRP) (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013;Duncan et al, 2014a;Lee et al, 2012; Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium et al, 2015;Nurnberger et al, 2014;Pedroso et al, 2012;Purcell et al, 2014; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Uddin et al, 2014).…”

“…As Flint and Kendler (2014) have demonstrated, candidate gene meta-analyses of MDD have been underpowered and the data thus far are consistent with a lack of significant findings in any meta-analysis. Using a different approach, Lee et al (2012) examined 188 MDD candidate genes and 178 biological gene sets related to these genes in a pathway analysis encompassing three GWAS data sets. Genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD after correction for multiple testing.…”