Genetically proxied gut microbiota, gut metabolites with risk of epilepsy and the subtypes: A bi-directional Mendelian randomization study

Abstract

BackgroundAn increasing number of observational studies have revealed an association among the gut microbiota, gut metabolites, and epilepsy. However, this association is easily influenced by confounders such as diet, and the causality of this association remains obscure.MethodsAiming to explore the causal relationship and ascertain specific gut microbe taxa for epilepsy, we conducted a bi-directional Mendelian randomization (MR) study based on the genome-wide association study (GWAS) data of epilepsy from the International League Against Epilepsy, with the gut microbiota GWAS results from MiBioGen, and summary-level GWAS data of gut microbiota-dependent metabolites trimethylamine N-oxide and its predecessors.ResultsNine phyla, 15 classes, 19 orders, 30 families, and 96 genera were analyzed. A suggestive association of host-genetic-driven increase in family Veillonellaceae with a higher risk of childhood absence epilepsy (odds ratio [OR]: 1.033, confidential interval [CI]: 1.015–1.051, PIVW = 0.0003), class Melainabacteria with a lower risk of generalized epilepsy with tonic-clonic seizures (OR = 0.986, CI = 0.979–0.994, PIVW = 0.0002), class Betaproteobacteria (OR = 0.958, CI = 0.937–0.979, PIVW = 0.0001), and order Burkholderiales (OR = 0.960, CI = 0.937–0.984, PIVW = 0.0010) with a lower risk of juvenile myoclonic epilepsy were identified after multiple-testing correction. Our sensitivity analysis revealed no evidence of pleiotropy, reverse causality, weak instrument bias, or heterogeneity.ConclusionThis is the first MR analysis to explore the potential causal relationship among the gut microbiota, metabolites, and epilepsy. Four gut microbiota features (two class levels, one order level, and one family level) were identified as potential interventional targets for patients with childhood absence epilepsy, generalized epilepsy with tonic-clonic seizures, and juvenile myoclonic epilepsy. Previous associations in numerous observational studies may had been interfered by confounders. More rigorous studies were needed to ascertain the relationship among the gut microbiota, metabolites, and epilepsy.

Gut Microbiota and Respiratory Infections: Insights from Mendelian Randomization

“…We followed three core assumptions to identify the IVs we needed. First, setting a statistical significance threshold of 1 × 10 −5 [ 24 ], screening out genetic variant SNPs that were strongly associated with the microbe but not directly associated with URTIs and LITIs, and excluding minor allele frequencies (MAFs) with a threshold of 0.01. We assessed the power of the instrumental variables using the F value [ 25 ], F = R 2 × (N – 1 − i)/(1 − R 2 ) × i , and IVs with an F less than 10 were excluded.…”

Role of inflammatory cytokine in mediating the effect of plasma lipidome on epilepsy: a mediation Mendelian randomization study

“…In the MR study, single nucleotide polymorphisms (SNPs) are regarded as an instrumental variables (IVs) to estimate the causal relationship between exposure and outcome (19). Previous studies have found the causal relationship between human blood metabolites, gut microbiota, circulating lipids, psychiatric disorders and epilepsy (20)(21)(22)(23)(24). In recent years, an increasing number of studies have examined the association between plasma lipidome and epilepsy, yet no research has explored this relationship at the genetic level.…”

The causal links between gut microbiota and COVID‐19: A Mendelian randomization study

“…The Mendelian randomization (MR) strategy is a technique used to investigate the possible causal link between exposure and outcome using instrumental variables (IVs). MR has been used to show that gut microbiota is correlated with a variety of diseases 17–20 . However, MR has not been employed to investigate the causal links between gut microbiota and COVID‐19 at present.…”

“…MR has been used to show that gut microbiota is correlated with a variety of diseases. [17][18][19][20] However, MR has not been employed to investigate the causal links between gut microbiota and COVID-19 at present. In this work, the GWAS data sets from an earlier study 21 were used to find the underlying linkages between gut microbiota and COVID-19 using a MR analysis.…”