Figure - available from: Frontiers in Immunology
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The challenge of thresholding continuous antibody measures. Blue represents the distribution of uninfected individuals; Red represents the distribution of infected individuals. The green, orange, and purple dashed lines represent cut-off points. This figure depicts the theoretical overlap in antibody distribution of uninfected individuals (represented in blue) and infected individuals (represented in red), and the coloured dashed lines denotes how cut-offs may be selected. For example, the green threshold would include all infected individuals as cases, but also include a proportion of uninfected individuals as cases. Alternatively, the purple threshold would result in no uninfected individuals included as cases, but miss some that are infected. The orange threshold may be ideal as it would minimise the proportion of individuals misclassified as either cases or controls. However, the true underlying two distributions are not separately observed and so can only ever be estimated from the overall distribution.
Source publication
The burden of infections on an individual and public health is profound. Many observational studies have shown a link between infections and the pathogenesis of disease; however a greater understanding of the role of host genetics is essential. Children from the longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children, had 14...
Citations
... Exposure data were from the Avon Longitudinal Study of Parents and Children Cohort (ALSPAC), containing 4,735 individuals with anti-H. pylori IgG levels (Chong et al., 2021). Outcome data for miscarriage were obtained from GWAS meta-analysis by Laisk et al. (Laisk et al., 2020), including 49,996 sporadic cases and 174,109 controls. ...
Background
Observational studies have reported that Helicobacter pylori (H. pylori) infection is associated with a series of pregnancy and neonatal outcomes. However, the results have been inconsistent, and the causal effect is unknown.
Methods
A two-sample Mendelian randomization (MR) study was performed using summary-level statistics for anti-H. pylori IgG levels from the Avon Longitudinal Study of Parents and Children Cohort. Outcome data for pregnancy (miscarriage, preeclampsia-eclampsia, gestational diabetes mellitus, placental abruption, premature rupture of membranes, postpartum hemorrhage) and neonates (birthweight, gestational age, and preterm birth) were sourced from genome-wide association meta-analysis as well as the FinnGen and Early Growth Genetics Consortium. Causal estimates were calculated by five methods including inverse variance weighted (IVW). The heterogeneity of instrumental variables was quantified by Cochran’s Q test, while sensitivity analyses were performed via MR-Egger, MR-PRESSO, and leave-one-out tests.
Results
IVW estimates suggested that genetically predicted anti-H. pylori IgG levels were significantly associated with increased risks of preeclampsia-eclampsia (odds ratio [OR] = 1.12, 95% confidence interval [CI] 1.01–1.24, P = 0.026) and premature rupture of membranes (OR = 1.17, 95% CI 1.05–1.30, P = 0.004). Similar results were obtained for preeclampsia-eclampsia from the MR-Egger method (OR = 1.32, 95% CI 1.06–1.64, P = 0.027) and for premature rupture of membranes from the weighted median method (OR = 1.22, 95% CI 1.06–1.41, P = 0.006). No significant causal effects were found for other outcomes. There was no obvious heterogeneity and horizontal pleiotropy across the MR analysis.
Conclusion
Our two-sample MR study demonstrated a causal relationship of H. pylori infection with preeclampsia-eclampsia and premature rupture of membranes. The findings confirm the epidemiological evidence on the adverse impact of H. pylori in pregnancy. Further studies are needed to elucidate the pathophysiological mechanisms and assess the effectiveness of pre-pregnancy screening and preventive eradication.
... In ALSPAC, participants were genotyped on the Illumina Human Hap550 Quad array. Additional information regarding genotyping procedures in ALSPAC is available in Paternoster et al. (2011) and Chong et al. (2021). In Add Health, participants were genotyped on the Illumina Human Omni1-Quad BeadChip and the Illumina Human Omni-2.5 Quad BeadChip. ...
Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.
This study investigates the potential causal relationships between the gut microbiome and herpesvirus-specific Immunoglobulin G (IgG) using Mendelian Randomization (MR) techniques. We aim to enhance the understanding of the susceptibility and pathogenesis of herpesvirus infections, contributing to the development of improved diagnostic, therapeutic, and preventive strategies. Our findings reveal that certain gut microbes, including members of the family. Lachnospiraceae and the genus. Methanobrevibacter , influence the levels of herpesvirus-specific IgG. These insights provide valuable information for potential future interventions targeting the gut microbiome to manage herpesvirus infections. Our study highlights the intricate relationship between the gut microbiome and herpesviruses, emphasizing the need for further research to explore the mechanisms underlying these associations and their implications for human health.
Nonalcoholic fatty liver disease (NAFLD) is the predominant cause of liver pathology. Current evidence highlights plasma proteins as potential therapeutic targets. However, their mechanistic roles in NAFLD remain unclear. This study investigated the involvement of specific plasma proteins and intermediate risk factors in NAFLD progression. Two-sample Mendelian randomization (MR) analysis was conducted to examine the association between plasma proteins and NAFLD. Colocalization analysis determined the shared causal variants between the identified proteins and NAFLD. The MR analysis was applied separately to proteins, risk factors, and NAFLD. Mediator shares were computed by detecting the correlations among these elements. Phenome-wide association studies (phewas) were utilized to assess the safety implications of targeting these proteins. Among 1,834 cis-protein quantitative trait loci (cis-pQTLs), after-FDR correction revealed correlations between the plasma levels of four gene-predicted proteins (CSPG3, CILP2, Apo-E, and GCKR) and NAFLD. Colocalization analysis indicated shared causal variants for CSPG3 and GCKR in NAFLD (posterior probability > 0.8). Out of the 22 risk factors screened for MR analysis, only 8 showed associations with NAFLD (p ≤ 0.05), while 4 linked to CSPG3 and GCKR. The mediator shares for these associations were calculated separately. Additionally, reverse MR analysis was performed on the pQTLs, risk factors, and NAFLD, which exhibited a causal relationship with forward MR analysis. Finally, phewas summarized the potential side effects of associated-targeting proteins, including CSPG3 and GCKR. Our research emphasized the potential therapeutic targets for NAFLD and provided modifiable risk factors for preventing NAFLD.
The association between Helicobacter pylori (H. pylori) infection and coronary heart disease (CHD) remains controversial, with an unclear causal link. This study employed bidirectional Mendelian randomization (MR) method, using H. pylori infection as the exposure, to investigate its causal relationship with CHD diagnosis, prognosis, and potential pathogenesis. H. pylori infection exhibited a causal association with body mass index (BMI) (β = 0.022; 95% CI 0.008–0.036; p = 0.001). Conversely, there was no discernible connection between H. pylori infection and the diagnosis of CHD (OR = 0.991; 95% CI 0.904–1.078; p = 0.842; IEU database; OR = 1.049; 95% CI 0.980–1.118; p = 0.178; FinnGen database) or CHD prognosis (OR = 0.999; 95% CI 0.997–1.001; p = 0.391; IEU database; OR = 1.022; 95% CI 0.922–1.123; p = 0.663; FinnGen database). Reverse MR analysis showed no causal effect of CHD on H. pylori infection. Our findings further support that H. pylori infection exerts a causal effect on CHD incidence, mediated by BMI. Consequently, eradicating or preventing H. pylori infection may provide an indirect clinical benefit for patients with CHD.
