The Causal Effects of Insomnia on Bipolar Disorder, Depression, and Schizophrenia: A Two-Sample Mendelian Randomization Study

Abstract

Psychiatric disorder, including bipolar disorder (BD), major depression (MDD), and schizophrenia (SCZ), affects millions of persons around the world. Understanding the disease causal mechanism underlying the three diseases and identifying the modifiable risk factors for them hold the key for the development of effective preventative and treatment strategies. We used a two-sample Mendelian randomization method to assess the causal effect of insomnia on the risk of BD, MDD, and SCZ in a European population. We collected one dataset of insomnia, three of BD, one of MDD, and three of SCZ and performed a meta-analysis for each trait, further verifying the analysis through extensive complementarity and sensitivity analysis. Among the three psychiatric disorders, we found that only insomnia is causally associated with MDD and that higher insomnia increases the risk of MDD. Specifically, the odds ratio of MDD increase of insomnia is estimated to be 1.408 [95% confidence interval (CI): 1.210–1.640, p = 1.03E-05] in the European population. The identified causal relationship between insomnia and MDD is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our results provide new evidence to support the causal effect of insomnia on MDD and pave ways for reducing the psychiatric disorder burden.

Potential genetic and epigenetic mechanisms in insomnia: A systematic review

“…In this framework, the 5‐HTTLPR S‐allele was found to predispose to risk of stress‐related insomnia (Huang et al, 2021) and depression‐related insomnia (Polito et al, 2015), as well as insomnia (Deuschle et al, 2010; Huang et al, 2021; Pallesen et al, 2019), although other findings do not confirm an involvement of the 5‐HTTLPR allele or of other genes involved in the biosynthesis of 5‐HT in insomnia (Hui et al, 2021; Mei et al, 2018; van Dalfsen & Markus, 2019).…”

“…Interestingly, some GWAS combined with Mendelian randomisation, a method of using measured variation in genes and to examine the causal effect of a modifiable exposure on disease in observational studies, started to give some important information about causality among insomnia and some mental/medical disorders. In this framework, GWAS SNPs genetic pre‐disposition to insomnia were found to have a significant causal effect on the risk of some mental conditions such as major depression, bipolar disorder type II, schizophrenia, autism spectrum disorder, alcohol, nicotine and opioid use, attention‐deficit/hyperactivity disorder, anxiety and post‐traumatic stress disorder (PTSD), and suicidal behaviours with reverse causality observed for major depression, nicotine use, and PTSD only (Jansen, Dolinoy, et al, 2019, Jansen, Watanabe, et al, 2019; Gao et al, 2019; Song et al, 2020; Pasman et al, 2020; Lewis et al, 2020; Cai et al, 2021; Huang et al, 2021; Carpena et al, 2021; Watanabe et al, 2022; Sun et al, 2022; Baranova et al, 2022; Zhou et al, 2022; Nassan et al, 2022). Similarly, GWAS SNPs genetic pre‐disposition to insomnia were found to have a significant causal one‐way effect on the risk of some medical conditions including: coronavirus disease 2019 (COVID‐19) susceptibility (Peng et al, 2022), cognitive impairment, neurodegenerative conditions (Sun et al, 2020; Zhang et al, 2022), cardiovascular diseases (Jansen, Dolinoy, et al, 2019; Jansen, Watanabe, et al, 2019; Jia et al, 2022; Liu et al, 2021; Zheng et al, 2020), diabetes, cardio‐metabolic risks (Gao et al, 2020; Jansen, Dolinoy, et al, 2019; Jansen, Watanabe, et al, 2019; Liu et al, 2021; Liu et al, 2022), increasing the odds of reporting pain conditions (An et al, 2022; Broberg et al, 2021; Chu et al, 2021; Shu et al, 2022) and for other medical conditions (Bao et al, 2022; He et al, 2022; Huo et al, 2021; Zha et al, 2021).…”

“…Recent studies have focused on G × E interactions, with Huang et al (2021) identifying significant main effects of 5‐HTTLPR (each S allele conferring a >80% increase in risk) and a significant gene–environment interaction for job‐related stress, such that for individuals with the SS genotype, those with high job‐related stress had higher insomnia risk and those with low job‐related stress had lower risk. Further, a recent review discussing predictors of insomnia included 5‐HTTLPR as a contributor to poor sleep via stress reactivity mechanisms (Harvey et al, 2014; Palagini, Biber, & Riemann, 2014; Palagini, Gemignani, et al, 2014).…”

Gut microbial features may influence antiviral IgG levels after vaccination against viral respiratory infectious diseases: the evidence from two-sample bidirectional mendelian randomization

“…We treated the gut microbial features as exposures and the four anti-virus IgG levels as outcomes to conduct a two-sample MR study. Based on the datasets, we followed a strict screening procedure to select IVs in other previous MR studies [ 26 , 27 ] (Fig. 1 ).…”

Unveiling Depression as a Significant Cause of Insomnia through NHANES Database and Mendelian Randomization Analysis

“…[4]Several studies have provided empirical evidence establishing a substantial correlation between insomnia and depression. [5,6], with the risk of depression increasing proportionally with the severity of insomnia. Nevertheless, certain studies have proposed that depression may not exert a signi cant impact on insomnia.…”