Abstract
Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide. Among the symptoms of MDD, sleep disturbance such as insomnia is prominent, and the first reason patients may seek professional help. However, the underlying pathophysiology of this comorbidity is still elusive. Recently, genome-wide association studies (GWAS) have begun to unveil the genetic background of several psychiatric disorders, including MDD and insomnia. Identifying the shared genomic risk loci between comorbid psychiatric disorders could be a valuable strategy to understanding their comorbidity. This study seeks to identify the shared genes and biological pathways between MDD and insomnia based on their shared genetic variants. First, we performed a meta-analysis based on the GWAS summary statistics of MDD and insomnia obtained from Psychiatric Genomics Consortium and UK Biobank, respectively. Next, we associated shared genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quantitative trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, a total of 719 shared genes were identified. Over half (51%) of them are protein-coding genes. Functional enrichment analysis shows that the most enriched biological pathways are related to epigenetic modification, sensory perception, and immunologic signatures. We also identified druggable targets using a network approach. Together, these results may provide insights into understanding the genetic predisposition and underlying biological pathways of comorbid MDD and insomnia symptoms.
Highlights
Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide, with a lifetime prevalence of 15% [1]
We conducted a genome-wide association meta-analysis of MDD and insomnia based on two previous genome-wide association studies (GWAS) studies: (1) Wray et al [16] identified 44 risk variants in 135,458 major depression cases versus 344,901 controls from seven cohorts
The most significant associated variant was rs113831554 (p = 1.64 × 10−22), which lies in the intronic region of MEIS1, a gene associated with restless legs syndrome (RLS) [40] (Supplementary Figure S2a)
Summary
Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide, with a lifetime prevalence of 15% [1]. Sleep disturbance is the core symptom of MDD that occurs in up to 90% of patients and is the first reason patients seek professional help [2,3]. Studies have shown that people with insomnia are more likely to develop depression and increase suicidal ideation if diagnosed with MDD [6,7]. Drugs and behavioral treatments for comorbid MDD and insomnia symptoms can improve both outcomes [8,9]. The relationship between MDD and insomnia may be bi-directional [10,11]
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