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.
Highlights
Major depressive disorder (MDD) is a common, disabling and frequently recurrent mood disorder that affects up to one in six individuals worldwide during their lifetime.[1]
Using these genes as input, GRAIL quantified their functional relationships using a text-based similarity measure (Supplementary Tables S3.2 and S3.3), and identified 11 keywords that are commonly associated with the MDD candidate genes in the literature: ‘serotonin’, ‘dopamine’, ‘NMDA (N-methyl-D-aspartate)’, ‘glutamate’, ‘neuron’, ‘GABA’, ‘adrenergic’, ‘agonist’, ‘cGMP’, ‘synaptic’ and ‘phosphodiesterase’
Genome-wide association analysis has transformed our understanding of the genetic etiology of various common and complex human disorders, but progress has been less rapid for studies of MDD
Summary
Major depressive disorder (MDD) is a common, disabling and frequently recurrent mood disorder that affects up to one in six individuals worldwide during their lifetime.[1] A number of antidepressant treatments exist, but due to modest rates of remission and substantial rates of recurrence, there is a pressing demand for new interventions with better efficacy. Identification of specific genetic risk factors could help to elucidate the neurobiological basis of MDD, which would facilitate the development of novel treatment and possibly even prevention strategies.[2]. Efforts to identify specific susceptibility genes in MDD have had limited success. Linkage studies have suggested several regions in the genome that may harbor susceptibility genes for MDD but generally without replication.[3]. Two recent linkage studies[4,5] have reported genomewide significant linkage to chromosome 3p26-3p25, with a peak signal near the metabotropic glutamate receptor 7 gene
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