Differing genetic variants associated with liver fat and their contrasting relationships with cardiovascular diseases and cancer.

BACKGROUND: The underlying mechanisms for the link between steatotic liver disease and cardiovascular and cancer outcomes are poorly understood. We aimed to use MRI-derived measures of liver fat and genetics to investigate causal mechanisms that link higher liver fat to various health outcomes. METHODS: We conducted a genome-wide association study on 37,358 UK Biobank participants to identify genetic variants associated with liver fat measured from MRI scans. We used Mendelian randomization approach to investigate the causal effect of liver fat on health outcomes independent of BMI, alcohol consumption and lipids using data from published GWAS and FinnGen. RESULTS: We identified 13 genetic variants associated with liver fat that showed differing risks to health outcomes. Genetic variants associated with impaired hepatic triglyceride export showed liver fat-increasing alleles to be correlated with a reduced risk of coronary artery disease and myocardial infarction but an elevated risk of type 2 diabetes; and variants associated with enhanced de novo lipogenesis showed liver fat-increasing alleles to be linked to a higher risk of myocardial infarction and coronary artery disease. Genetically higher liver fat content increased the risk of non-alcohol liver cirrhosis, hepatocellular and Intrahepatic bile ducts and gallbladder cancers, exhibiting a dose-dependent relationship, irrespective of the mechanism. CONCLUSION: This study provides fresh insight into the heterogeneous effect of liver fat on health outcomes. It challenges the notion that liver fat per se is an independent risk factor for cardiovascular disease, underscoring the dependency of this association on the specific mechanisms that drive fat accumulation in the liver. However, excess liver fat, regardless of how achieved, appears to be causally linked to liver cirrhosis and cancers in a dose dependent manner. IMPACT AND IMPLICATION: This research advances our understanding of the heterogeneity in mechanisms influencing liver fat accumulation, providing new insights into how liver fat accumulation may impact various health outcomes. The findings challenge the notion that liver fat is an independent risk factor for cardiovascular disease and highlight the mechanistic effect of some genetic variants on fat accumulation and the development of cardiovascular diseases. This study is of particular importance for healthcare professionals including physicians and researchers as well as patients as it allows for more targeted and personalised treatment by understanding the relationship between liver fat and various health outcomes. The findings emphasise the need for a personalised management approach and a reshaping of risk assessment criteria. It also provides room for prioritising a clinical intervention aimed at reducing liver fat content (likely by intentional weight loss, however, achieved) that could help protect against liver related fibrosis and cancer.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian Randomisation study.

Background: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. Aims: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. Methods: We conducted a sex-specific two-sample Mendelian randomisation study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e., aSAH and unruptured IA combined) as outcomes. Results: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (P-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (P-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (P-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Conclusions: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Comprehensive analysis of MAPK genes in the prognosis, immune characteristics, and drug treatment of renal clear cell carcinoma using bioinformatic analysis and Mendelian randomization.

Mitogen-activated protein kinase (MAPK) signalling is vitally important in tumour development and progression. This study is the first to comprehensively analyse the role of MAPK-family genes in the progression, prognosis, immune-cell infiltration, methylation, and potential therapeutic value drug candidates in ccRCC. We identified a novel prognostic panel of six MAPK-signature genes (MAP3K12, MAP3K1, MAP3K5, MAPK1, MAPK8, MAPK9), and introduced a robust MAPK-signature risk model for predicting ccRCC prognosis. Model construction, evaluation, and external validation using datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database demonstrated its stability, as well as high sensitivity and specificity. Enrichment analysis suggested the participation of immune-mediated mechanism in MAPK dysregulation in ccRCC. Immune-infiltration analysis confirmed the relationship and revealed that the MAPK-signature risk model might stratify immunotherapy response in ccRCC, which was verified in drug sensitivity analysis and validated in external ccRCC immunotherapy dataset (GSE67501). Potential therapeutic drug predictions for key MAPKs using DSigDB, Network Analyst, CTD, and DGIdb were subsequently verified by molecular docking with AutoDock Vina and PyMol. Mendelian randomization further demonstrated the possibilities of the MAPK-signature genes as targets for therapeutic drugs in ccRCC. Methylation analysis using UALCAN and MethSurv revealed the participation of epigenetic modifications in dysregulation and survival difference of MAPK pathway in ccRCC. Among the key MAPKs, MAP3K12 exhibited the highest significance, indicating its independent prognostic value as single gene in ccRCC. Knockout and overexpression validation experiments in vitro and in vivo found that MAP3K12 acted as a promoter of tumour progression in RCC, suggesting a pivotal role for MAP3K12 in the proliferation, migration, and invasion of RCC cells. Our findings proposed the potential of MAPK-signature genes as biomarkers for prognosis and therapy response, as well as targets for therapeutic drugs in ccRCC.

Integrating plasma proteomics with genome-wide association data to identify novel drug targets for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic disease that includes Crohn's disease (CD) and ulcerative colitis (UC). Although genome-wide association studies (GWASs) have identified many relevant genetic risk loci, the impact of these loci on protein abundance and their potential utility as clinical therapeutic targets remain uncertain. Therefore, this study aimed to investigate the pathogenesis of IBD and identify effective therapeutic targets through a comprehensive and integrated analysis. We systematically integrated GWAS data related to IBD, UC and CD (N = 25,305) by the study of de Lange KM with the human blood proteome (N = 7213) by the Atherosclerosis Risk in Communities (ARIC) study. Proteome-wide association study (PWAS), mendelian randomisation (MR) and Bayesian colocalisation analysis were used to identify proteins contributing to the risk of IBD. Integrative analysis revealed that genetic variations in IBD, UC and CD affected the abundance of five (ERAP2, RIPK2, TALDO1, CADM2 and RHOC), three (VSIR, HGFAC and CADM2) and two (MST1 and FLRT3) cis-regulated plasma proteins, respectively (P < 0.05). Among the proteins identified via Bayesian colocalisation analysis, CADM2 was found to be an important common protein between IBD and UC. A drug and five druggable target genes were identified from DGIdb after Bayesian colocalisation analysis. Our study's findings from genetic and proteomic approaches have identified compelling proteins that may serve as important leads for future functional studies and potential drug targets for IBD (UC and CD).

Association Between Periodontitis and Preeclampsia: A Bidirectional Mendelian Randomisation Analysis.

OBJECTIVES: Studies have increasingly focussed on the relationship between periodontitis (PD) and preeclampsia (PE). However, conclusions have not been consistent, and it is unclear whether any causal relationship exists between them and whether causality is bidirectional. This study employed Mendelian randomisation (MR) analysis to investigate the potential bidirectional causal relationship between PD and PE. METHODS: Genetic variants strongly linked to PD (17,353 cases and 28,210 controls), chronic periodontitis (CP; 1817 cases and 2215 controls), aggressive periodontitis (AgP; 851 cases and 6580 controls), and PE (7212 cases and 194,266 controls) in the genome-wide association study (GWAS) of European ancestry were used as instrumental variables (IVs). Inverse variance weighting (IVW) served as the primary method for causal inference. MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) was utilised to analyse horizontal pleiotropy. Cochrane Q tests and leave-one-out analyses were used to assess heterogeneity and stability amongst IVs. RESULTS: The MR analysis revealed no causal impacts of PD or its 2 subtypes-CP and AgP-on PE. Similarly, no significant causal effect of PE on PD was found in the reverse-MR analysis (IVW odds ratio, 0.97; 95% confidence interval, 0.91-1.05; P = .58). The findings from MR-Egger, weighted median, weighted mode, and the simple modelling approaches, as well as the pleiotropy and sensitivity analyses, aligned with those of the IVW method. CONCLUSIONS: The MR analysis suggests no bidirectional causal relationship between PD and PE; hence, PD and PE might not increase or prevent the risk of one other. CLINICAL RELEVANCE: Genetically, periodontitis or its subtypes chronic periodontitis and aggressive periodontitis may not require specific clinical attention to prevent the development of preeclampsia.

Telomere length in relation to fecundability and use of assisted reproductive technologies: the Norwegian Mother, Father, and Child Cohort Study.

In women, shorter telomeres have been reported to be associated with conditions such as endometriosis and polycystic ovary syndrome, whereas other studies have reported the opposite. In men, studies mostly report associations between shorter telomeres and sperm quality. To our knowledge, no studies have thus far investigated the associations between TL and fecundability or the use of ART. This study is based on the Norwegian Mother, Father, and Child Cohort (MoBa) Study and uses data from the Medical Birth Registry of Norway (MBRN). We included women (24,645 with genotype data and 1,054 with TL measurements) and men (18,339 with genotype data and 965 with TL measurements) participating between 1998 and 2008. We investigated the associations between leukocyte TL and fecundability, infertility, and the use of ART. We also repeated the analyses using instrumental variables for TL, including genetic risk scores for TL and genetically predicted TL. Approximately 11% of couples had experienced infertility and 4% had used ART. TL was not associated with fecundability among women (fecundability ratio [FR], 0.98; 95% confidence interval [CI], 0.92-1.04) or men (FR, 0.99; CI, 0.93-1.06), nor with infertility among women (odds ratio [OR], 1.03; CI, 0.85-1.24) or men (OR, 1.05; CI, 0.87-1.28). We observed an increased likelihood of using ART with increasing TL among men (OR, 1.22; CI, 1.03-1.46), but not among women (OR, 1.10; CI, 0.92-1.31). No significant associations were observed using the instrumental variables. Our results indicate that TL is a poor biomarker of fecundability, infertility and use of ART in MoBa. Additional studies are required to replicate the association observed between TL and ART in men.

Genetic causal relationship between gut microbiota and basal cell carcinoma: A two-sample mendelian randomization study.

OBJECTIVE: Research has previously established connections between the intestinal microbiome and the progression of some cancers. However, there is a noticeable gap in the literature in regard to using Mendelian randomisation (MR) to delve into potential causal relationships between the gut microbiota (GM) and basal cell carcinoma (BCC). Therefore, the purpose of our study was to use MR to explore the causal relationship between four kinds of GM (Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae) and BCC. METHODS: We used genome-wide association study (GWAS) data and MR to explore the causal relationship between four kinds of GM and BCC. This study primarily employed the random effect inverse variance weighted (IVW) model for analysis, as complemented by additional methods including the simple mode, weighted median, weighted mode and MR‒Egger methods. We used heterogeneity and horizontal multiplicity to judge the reliability of each analysis. MR-PRESSO was mainly used to detect and correct outliers. RESULTS: The random-effects IVW results showed that Bacteroides (OR = 0.936, 95% CI = 0.787-1.113, p = 0.455), Streptococcus (OR = 0.974, 95% CI = 0.875-1.083, p = 0.629), Proteobacteria (OR = 1.113, 95% CI = 0.977-1.267, p = 0.106) and Lachnospiraceae (OR = 1.027, 95% CI = 0.899-1.173, p = 0.688) had no genetic causal relationship with BCC. All analyses revealed no horizontal pleiotropy, heterogeneity or outliers. CONCLUSION: We found that Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae do not increase the incidence of BCC at the genetic level, which provides new insight for the study of GM and BCC.

Causal effects between gut microbiota and endometriosis: a two-sample Mendelian randomisation study.

BACKGROUND: Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship of the association remains to be investigated. METHOD: Genome-wide association study (GWAS) data of GM was obtained from the MiBioGen consortium, and GWAS for endometriosis data was from the FinnGen consortium. Initially, a two-sample Mendelian randomisation (MR) analysis was performed to identify specific bacteria associated with endometriosis. Inverse variance-weighted (IVW) was used as the main MR analysis to infer causal relationships. The other four popular MR methods including MR-Egger regression, weighted mode, weighted median, and simple mode were used for secondary confirmation. Subsequently, these selected bacteria were employed as exposure to investigate their causal effects on six sub-types of endometriosis. Furthermore, reverse MR analysis was implemented to evaluate the reverse causal effects. Cochran's Q statistics was used to test the heterogeneity of instrumental variables (IVs); MR-Egger regression was used to test horizontal pleiotropy; MR-PRESSO and leave-one-out sensitivity analysis were applied to find significant outliers. RESULT: A total of 1131 single nucleotide polymorphisms (SNPs) were collected as IVs for 196 GM taxa with endometriosis as the outcome. We identified 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera (Rikenellaceae RC9 gut group, Eubacterium ruminantium group, Faecalibacterium, Peptococcus, Clostridium sensu stricto 1, and Ruminococcaceae UCG005). Utilizing the Bonferroni method, we identified phylum Cyanobacteria as the strongest associated GM taxa. Subsequently, 6 significant causal effects were uncovered between the 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, no reverse causal relationship was found. Further, no horizontal pleiotropy and no significant outliers were detected in the sensitive analysis. CONCLUSIONS: This MR analysis revealed significant causal effects between GM and endometriosis and phylum Cyanobacteria had the strongest association.

The imbalance of gut microbiota (GM) is suggested to be involved in the development of endometriosis while the causal relationship between GM and endometriosis remains undetermined. This two-sample mendelian randomisation analysis firstly demonstrated the potential association between GM and the risk of endometriosis including 6 sub-types. We revealed 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera while Phylum Cyanobacteria was the strongest associated GM taxa by using Bonferroni method. Meanwhile, we identified 6 significant causal effects between 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, the result from reverse MR analysis showed that there was no causal effect of endometriosis on the identified specific GM taxa. Thus, we revealed the causal relationship between GM and endometriosis. It is necessary to further study its potential mechanism, which may contribute to the prevention and treatment of Endometriosis.

Association between COVID-19 and the Risk of Vascular Dementia: A Mendelian Randomisation Study of the Potential Cognitive Sequela of COVID-19.

A growing body of observational studies and Mendelian Randomisation analyses suggest an increased risk of Alzheimer's disease and dementia following COVID-19 infection. However, evidence on the potential association between COVID-19 and vascular dementia, which is plausible given the vascular complications of COVID-19 infection, is still limited. In this study, we conducted a two-sample Mendelian Randomisation analysis to examine the potential causal relationship between COVID-19 phenotypes and the risk of vascular dementia, using summary data from large-scale GWASs. The two-sample Mendelian Randomisation analysis did not detect any significant associations of COVID-19 infection, COVID-19 hospitalisation, or critical COVID-19 with the risk of vascular dementia, with weighted average ß values of -0.29 (95% CI: -0.84, 0.26; p = 0.301), -0.12 (95% CI: -0.36, 0.13; p = 0.345), and -0.07 (95% CI: -0.23, 0.09; p = 0.374), respectively. Our findings do not support the hypothesis that vascular dementia is one of the long-term sequelae of COVID-19.

The association between polyunsaturated fatty acids and periodontitis: NHANES 2011-2014 and Mendelian randomisation analysis.

BACKGROUND: We aimed to explore the association and potential causality between polyunsaturated fatty acids concentrations and the risk of periodontal disease. MATERIALS AND METHODS: Data were collected from the 2011-2014 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression analysis and restricted cubic spline (RCS) analysis were used to analyse the associations of the concentrations of omega-3 and omega-6 fatty acids and the omega-6/omega-3 fatty acids ratio with the risk of periodontitis. E-value and propensity score matching (PSM) analyses were used for sensitivity analyses. In addition, two-sample Mendelian randomisation (MR) analyses were performed to assess the potential causal impact of the concentrations of those fatty acids on periodontitis risk. RESULTS: A total of 2462 participants from the NHANES were included. Logistic regression analysis revealed that high omega-3 fatty acids levels were negatively associated with the risk of developing periodontitis (P < 0.05), while the omega-6/omega-3 fatty acids ratio was positively associated with the risk of developing periodontitis (P < 0.05). There was no significant association between omega-6 concentrations and the risk of periodontitis. The findings mentioned above were confirmed by analysis following a 1:1 PSM. Furthermore, MR examination of the two samples indicated no possible causal link between the risk of periodontitis and the concentrations of omega-3 or omega-6 fatty acids or the ratio of omega-6 to omega-3 fatty acids (P > 0.05). CONCLUSION: Although omega-3 fatty acids and the omega-6/omega-3 fatty acids ratio were associated with the risk of periodontitis in cross-sectional studies, the MR results did not support a causal relationship between them. Therefore, there is no indication that an increase in the omega-3 fatty acids concentration or a decrease in the omega-6/omega-3 fatty acids ratio may be beneficial for preventing periodontitis.

Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics.

BACKGROUND: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. METHODS: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. FINDINGS: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. INTERPRETATION: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer. FUNDING: This work was supported by Cancer Research UK (grant no. C8221/A29017).

The effect of heavy smoking on retirement risk: A mendelian randomisation analysis.

BACKGROUND AND AIMS: The extent to which heavy smoking and retirement risk are causally related remains to be determined. To overcome the endogeneity of heavy smoking behaviour, we employed a novel approach by exploiting the genetic predisposition to heavy smoking, as measured with a polygenic risk score (PGS), in a Mendelian Randomisation approach. METHODS: 8164 participants (mean age 68.86 years) from the English Longitudinal Study of Ageing had complete data on smoking behaviour, employment and a heavy smoking PGS. Heavy smoking was indexed as smoking at least 20 cigarettes a day. A time-to-event Mendelian Randomization (MR) analysis, using a complementary log-log (cloglog) link function, was employed to model the retirement risk. RESULTS: Our results show that being a heavy smoker significantly increases the risk of retirement (ß = 1.324, standard error = 0.622, p < 0.05). Results were robust to a battery of checks and a placebo analysis considering the never-smokers. CONCLUSIONS: Overall, our findings support a causal pathway from heavy smoking to earlier retirement.

Proteome-Wide Mendelian Randomisation Identifies Causal Links of Plasma Proteins With Periodontitis.

OBJECTIVE: Periodontitis is a complex and multifactorial disease and it is challenging to decipher its underlying causes and mechanisms. This study attempted to explore potential circulating proteins in connection to periodontitis through proteome-wide Mendelian randomisation (MR). METHODS: We analysed 1722 circulating proteins to identify prospective drug targets for tackling periodontitis, using the genomic dataset from the FinnGen study. Two-sample MR was conducted to evaluate the bidirectional relationship between circulating proteins and periodontitis risk. A dataset from the UK Biobank was used to validate the findings. Single-cell analysis was performed to assess the cellular expression of the identified proteins within gingival tissues. RESULTS: MR analyses found that genetically predicted circulating levels of von Willebrand factor A domain-containing 1 (von Willebrand factor A domain containing 1 [VWA1], odds ratios: 0.94, 95% CI 0.92-0.97, P = 1.28 × 10-5) were inversely associated with periodontitis. In contrast, the level of growth differentiation factor 15 (growth differentiation factor 15 [GDF15], odds ratios: 1.05, 95% CI 1.02-1.07, P = 2.12 × 10-5) might be associated with an increased risk of periodontitis. Single-cell analysis indicated that VWA1 was primarily expressed in endothelial cells of healthy gingival tissues, while the main source of GDF15 was not derived from periodontal cells. CONCLUSIONS: The present study suggests that certain plasma proteins like VWA1 and GDF15 may be potentially indicative of the risk and susceptibility to periodontitis. These proteins could possibly be the potential therapeutic targets for treating periodontitis, and further investigation is highly warranted.

Coeliac disease and type 2 diabetes risk: a nationwide matched cohort and Mendelian randomisation study.

AIMS/HYPOTHESIS: While the association between coeliac disease and type 1 diabetes is well documented, the association of coeliac disease with type 2 diabetes risk remains undetermined. We conducted a nationwide cohort and Mendelian randomisation analysis to investigate this link. METHODS: This nationwide matched cohort used data from the Swedish ESPRESSO cohort including 46,150 individuals with coeliac disease and 219,763 matched individuals in the comparator group selected from the general population, followed up from 1969 to 2021. Data from 9053 individuals with coeliac disease who underwent a second biopsy were used to examine the association between persistent villous atrophy and type 2 diabetes. Multivariable Cox regression was employed to estimate the associations. In Mendelian randomisation analysis, 37 independent genetic variants associated with clinically diagnosed coeliac disease at p<5×10-8 were used to proxy genetic liability to coeliac disease. Summary-level data for type 2 diabetes were obtained from the DIAGRAM consortium (80,154 cases) and the FinnGen study (42,593 cases). RESULTS: Over a median 15.7 years' follow-up, there were 6132 (13.3%) and 30,138 (13.7%) incident cases of type 2 diabetes in people with coeliac disease and comparator individuals, respectively. Those with coeliac disease were not at increased risk of incident type 2 diabetes with an HR of 1.00 (95% CI 0.97, 1.03) compared with comparator individuals. Persistent villous atrophy was not associated with an increased risk of type 2 diabetes compared with mucosal healing among participants with coeliac disease (HR 1.02, 95% CI 0.90, 1.16). Genetic liability to coeliac disease was not associated with type 2 diabetes in DIAGRAM (OR 1.01, 95% CI 0.99, 1.03) or in FinnGen (OR 1.01, 95% CI 0.99-1.04). CONCLUSIONS/INTERPRETATION: Coeliac disease was not associated with type 2 diabetes risk.

Glucagon-like-peptide 1 receptor agonism and attempted suicide: A Mendelian randomisation study to assess a potential causal association.

Glucagon-like-peptide 1 receptor agonists (GLP-1RA) have transformed type 2 diabetes (T2D) and obesity management. Multiple regulatory agencies are investigating reported associations between GLP1-RA and increased suicide attempts (SA), but observational data may be prone to confounding. Randomised control trials (RCT) of GLP-1RA were largely undertaken in people at lower risk of SA. Real-world data suggest semaglutide use associates with reduced suicidal ideation and depression but was under-powered to statistically assess risk of SA. Mendelian randomisation (MR) leverages genetic instrument(s) to infer potential causal association between an exposure and an outcome. We undertook MR using missense variants in the gene encoding GLP1R that improve glycemia, lower T2D risk and/or lower BMI, to investigate potential causal association between GLP-1RA and SA. In people of European ancestry, MR did not find evidence genetically proxied GLP1RA increased SA in a general population cohort: (rs10305492, exposure: HbA1c, odds ratio [OR] and 95% confidence interval [CI]: 1.38, 0.41-4.62, p = .60), (rs10305492, exposure: FG, OR 1.27, 0.52-3.13, p = .60) and (rs1042044, exposure BMI, OR 0.30, 0.06-1.48) with concordant results in a multi-ancestry SA case-control cohort. In conclusion, we did not find MR evidence that increased GLP-1RA impacts SA. This awaits confirmation with RCT and real-world data.

Non-linear Mendelian randomization: detection of biases using negative controls with a focus on BMI, Vitamin D and LDL cholesterol.

Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the "residual" exposure). These "local" causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method-the doubly-ranked method-has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects-that of low-density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest there should be extensive simulation and empirical methodological examination of performance of both methods for NLMR under different conditions before further use of these methods. In the interim, use of NLMR methods needs justification, and a number of sanity checks (such as analysis of negative and positive control outcomes, sensitivity analyses excluding removal of strata at the extremes of the distribution, examination of biological plausibility and triangulation of results) should be performed.

Assessing Causal Relationships Between Periodontitis and Non-alcoholic Fatty Liver Disease: A Two-Sample Bidirectional Mendelian Randomisation Study.

PURPOSE: To investigate the causality between periodontitis and non-alcoholic fatty liver disease (NAFLD) using a two-sample bidirectional Mendelian randomisation (MR) analysis. MATERIALS AND METHODS: Genetic variations in periodontitis and NAFLD were acquired from genome-wide association studies (GWAS) using the Gene-Lifestyle Interaction in Dental Endpoints, a large-scale meta-analysis, and FinnGen consortia. Data from the first two databases were used to explore the causal relationship between periodontitis and NAFLD ("discovery stage"), and the data from FinnGen was used to validate our results ("validation stage"). We initially performed MR analysis using 5 single nucleotide polymorphisms (SNPs) in the discovery samples and 18 in the replicate samples as genetic instruments for periodontitis to investigate the causative impact of periodontitis on NAFLD. We then conducted a reverse MR analysis using 6 SNPs in the discovery samples and 4 in the replicate samples as genetic instruments for NAFLD to assess the causative impact of NAFLD on periodontitis. We further implemented heterogeneity and sensitivity analyses to assess the reliability of the MR results. RESULTS: Periodontitis was not causally related to NAFLD (odds ratio [OR] = 1.036, 95% CI: 0.914-1.175, p = 0.578 in the discovery stage; OR = 1.070, 95% CI: 0.935-1.224, p = 0.327 in the validation stage), and NAFLD was not causally linked with periodontitis (OR = 1.059, 95% CI: 0.916-1.225, p = 0.439 in the discovery stage; OR = 0.993, 95% CI: 0.896-1.102, p = 0.901 in the validation stage). No heterogeneity was observed among the selected SNPs. Sensitivity analyses demonstrated the absence of pleiotropy and the reliability of our MR results. CONCLUSION: The present MR analysis showed no genetic evidence for a cause-and-effect relationship between periodontitis and NAFLD. Periodontitis may not directly influence the development of NAFLD and vice versa.

Association Between Periodontitis and Adverse Pregnancy Outcomes: Two-Sample Mendelian Randomisation Study.

AIM: This Mendelian randomisation (MR) study endeavoured to delineate the causal relationship between periodontitis and adverse pregnancy outcomes (APOs), encompassing low birthweight (LBW), pre-term birth (PTB), stillbirth, miscarriage, and gestational hypertension (GH). METHODS: Utilising genetic instruments for periodontitis (acute and chronic periodontitis) from the Genome-Wide Association Study (GWAS) database among individuals of European descent, this study explored the causal relationship with adverse pregnancy outcomes, and vice versa. The Inverse Variance Weighted (IVW) method was employed as the primary analytical approach to assess causality, with MR-Egger serving as a sensitivity analysis method. RESULTS: The primary analytical method employed in this study, IVW, did not reveal any impact of periodontitis (acute and chronic periodontitis) on PTB, stillbirth, miscarriage, and gestational hypertension, and vice versa. Heterogeneity testing using the MR-Egger method confirmed the null causal hypothesis, with odds ratios (OR) approximating 1, and P-values exceeding 0.05. Notably, the results from the IVW analysis (OR 1.410, CI 1.039-1.915, P-value 0.028) indicate statistically significant evidence supporting a causal relationship between chronic periodontitis and LBW. However, caution is advised in interpreting the causal relationship, considering the non-significant P-values obtained from other methods. CONCLUSION: Within the limitations of this MR study, the findings do not support the influence of periodontitis on LBW, PTB, stillbirth, miscarriage, and GH, nor vice versa.