Causal Effect Of Genetic Liability Research Articles

Association between prescription opioid use and heart failure: Cohort studies and Mendelian randomization analysis

BackgroundPrescription opioid use (POU) has been shown to lead to cardiovascular disease (CVD), but its association with heart failure has not been well studied. We investigated the potential causal association between POU and HF using cohort studies and Mendelian Randomization (MR) analysis. MethodsInitially, we examined the longitudinal association between POU and HF using the data from the Health and Retirement Study (HRS) and the UK biobank. Next, we employed a two-sample MR analysis using summary statistics from genome-wide association studies (GWAS) to assess the potential causal associations between POU and HF. ResultsDuring a median of 3.8 and 13.8 years of follow-up, there were 441(8.04 per 1000 person-year) and 16,170 (3.96 per 1000 person-year) HF cases in the HRS and the UK biobank, respectively. After adjusting for covariates, participants who used prescription opioids had a 32% increased risk of developing HF, compared with non-users (HR = 1.32, 95%CI: 1.26–1.38, P < 0.001). In the MR analysis, summary statistics for POU were obtained from 78,808 UK Biobank study participants, and summary data for HF were obtained from 218,792 participants of a European population. A causal effect of genetic liability for POU on an increased risk of HF (OR = 1.16, 95% CI = 1.06, 1.27, P = 0.001) was suggested. The results were generally consistent in the sensitivity analysis, and no pleiotropy or heterogeneity were observed. ConclusionsPOU is associated with a high risk of HF. Our findings provide new insight into prescription opioid use among populations at risk of heart failure. More studies are needed to validate our results and further investigate the underlying mechanisms.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study

BackgroundThe epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators.MethodsUsing summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy.ResultsUnivariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05).ConclusionsOur findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD–atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD–CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.

P049 Genetic liability to rheumatoid arthritis and the risk of cardiometabolic diseases

Abstract Background/Aims Patients with rheumatoid arthritis (RA) are at an increased risk of comorbidities. Previous studies have reported a positive association between RA and cardiometabolic disease risk. However, few causal inference studies have addressed the different serological subtypes of RA and their association with cardiometabolic disease risk. This Mendelian randomisation (MR) study was conducted to offer insight into the causal pathway underlying this association. Methods A two-sample MR analysis was conducted using genetic variants as instrumental variables (IVs) to estimate the causal effect of genetic liability to RA and its serological subsets (seropositive and seronegative) on cardiometabolic disease risk including hypertension, coronary artery disease (CAD), atrial fibrillation, heart failure, stroke, and type 2 diabetes mellitus (T2DM). IVs were obtained from two genome-wide association studies (GWASs) for RA (53,663 cases and 1,064,978 controls [n =177 IVs]). Summary statistics were stratified for serological status including seropositive RA (RA+; 35,240 cases, [n = 195 IVs]), and seronegative RA (RA−; 8,515 cases, [n = 12 IVs]). Both subsets were compared to 990,155 controls. Summary statistics for cardiometabolic diseases were extracted from GWASs of European ancestries. Results The inverse-variance weighted (IVW) model showed a positive association between genetic liability to RA and the risk of CAD, heart failure, and T2DM; CAD, (Odds ratio [OR] = 1.04; 95% confidence interval [CI] 1.01-1.06; P-value [P] = 2.7210-3, heart failure, OR = 1.03; 95% CI 1.01-1.06; P = 0.018, and T2DM, OR = 1.08; 95% CI 1.05-1.11; P = 4.6310-8.). A similar association direction was observed between genetic liability to RA+ and the risk of CAD and T2DM; CAD, (OR = 1.02; 95% CI 1.01-1.04; P = 0.009, T2DM, OR = 1.05; 95% CI 1.03-1.07; P = 3.9110-7). Genetic liability to RA− was positively associated with T2DM risk; (OR = 1.09; 95% CI 1.02-1.16; P = 0.011). Conclusion In this MR study, a positive association of genetic liability to RA was demonstrated with CAD, heart failure and T2DM risk. Genetic liability to RA+ was associated with an increased risk of CAD and T2DM risk while genetic liability to RA− was positively associated with T2DM risk. Future research should investigate genetic architecture of RA including its serological subsets with cardiometabolic diseases to delineate the genes associated with these comorbidities. Disclosure S. Alduhayhi: None. M. Soomro: None. S. Zhao: None. A. Barton: None. A. Morris: None. J. Bowes: None.

Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis.

The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear. By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders. SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07–1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06–1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04–1.18, p = 1.84 × 10−3). We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

Inflammatory Bowel Disease and Skin Cancer: A Two-Sample Mendelian Randomization Analysis.

Background: At present, numerous clinical studies suggest a correlation between inflammatory bowel disease (IBD) and skin cancer. However, some articles present differing views that IBD does not increase the risk of skin cancer. The presence of potential reverse causality and residual confounding is inherent in conventional observational studies. Thus, this study used a two-sample Mendelian randomization (MR) study design to estimate the causal effect of IBD on the risk of skin cancer, including cutaneous malignant melanoma (CMM, also named melanoma skin cancer) and nonmelanoma skin cancer (NMSC). Design: In this study, a two-sample MR analysis was used to estimate the causal effect of IBD on skin cancer outcomes. The inverse-variance weighted (IVW) method was used as the main MR analysis, with multiple sensitivity analyses conducted to assess the robustness of findings. Results: In examining the association between IBD and NMSC, all p-values of the IVW methods were found to be <0.05, providing evidence for a causal effect of IBD on an increased risk of NMSC. However, IVW for IBD on CMM yielded p-values >0.05, indicating no causal relationship between IBD and CMM. These findings were consistent across other MR methods, with no evidence of pleiotropy or heterogeneity. Sensitivity analyses confirmed the robustness of our results. Conclusion: Using MR analysis, we found evidence for a causal effect of genetic liability for IBD on an increased risk of NMSC. However, our study did not find sufficient evidence to support a significant impact of IBD on CMM outcomes.

Observational and genetic analyses of the bidirectional relationship between depression and hypertension

BackgroundWhile the association between depression and hypertension has been extensively investigated, the pattern and nature of such association remain inconclusive. We sought to investigate the bidirectional relationship between depression and hypertension and its causal. MethodsWe first performed observational analyses using longitudinal data from the UK Biobank. We then performed genetic analyses leveraging summary statistics from large-scale genome-wide association studies (GWASs) conducted in European ancestry for depression and hypertension. ResultsObservational analysis suggested a significant bidirectional phenotypic association between depression and hypertension (Depression → Hypertension: HR = 1.27, 95 % CI: 1.19, 1.36; Hypertension → Depression: HR = 1.65, 95 % CI: 1.58, 1.72). Linkage disequilibrium score regression demonstrated a positive genetic correlation between the two conditions (rg=0.15, P = 5.75 × 10−10). Bidirectional two-sample Mendelian randomization (MR) suggested that genetic liability to depression was significantly associated with an increased risk of hypertension (OR = 1.27, 95 % CI: 1.12, 1.43), while the genetic liability to hypertension was not associated with the risk of depression (OR = 1.01, 95 % CI: 0.99, 1.03). Multivariate MR, after adjusting for smoking, drinking, and body mass index, further supported an independent causal effect of genetic liability to depression on hypertension risk (OR = 1.10, 95 % CI: 1.02, 1.18). Limitations(1) interference of confounders, (2) absence of adequate statistical power, and (3) limitation to European populations. ConclusionOur study indicates depression is a causal risk factor for hypertension, whereas the reverse maybe not. Findings support that prevention of depression might help in decreasing hypertension incidence.

A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke

Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a threshold P value (P) of <5 × 10−7, clumping distance of 1000 kilobase (Mb) and r2 < 0.01. Genetic association estimates for IS were obtained from the MEGASTROKE consortium (Ncases = 34,217, Ncontrols = 406,111) for European ancestry individuals and from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) (Ncases = 3734, Ncontrols = 18,317) for African ancestry individuals. We used the inverse-variance weighted (IVW) approach as the main analysis and performed MR-Egger and the weighted median methods as pleiotropy-robust sensitivity analyses. In European ancestry individuals, we found evidence of an association between genetic liability to PTSD avoidance, and PCL-Total and increased IS risk (odds ratio (OR)1.04, 95% Confidence Interval (CI) 1.007–1.077, P = 0.017 for avoidance and (OR 1.02, 95% CI 1.010–1.040, P = 7.6 × 10−4 for PCL total). In African ancestry individuals, we found evidence of an association between genetically liability to PCL-Total and reduced IS risk (OR 0.95 (95% CI 0.923–0.991, P = 0.01) and hyperarousal (OR 0.83 (95% CI 0.691–0.991, P = 0.039) but no association was observed for PTSD case-control, avoidance, or re-experiencing. Similar estimates were obtained with MR sensitivity analyses. Our findings suggest that specific sub-phenotypes of PTSD, such as hyperarousal, avoidance, PCL total, may have a causal effect on people of European and African ancestry’s risk of IS. This shows that the molecular mechanisms behind the relationship between IS and PTSD may be connected to symptoms of hyperarousal and avoidance. To clarify the precise biological mechanisms involved and how they may vary between populations, more research is required.

REAL WORLD AND MENDELIAN RANDOMIZATION ANALYSES OF THE IMPACT OF AUTOIMMUNE DISEASE ON CLINICAL CHARACTERISTICS IN LYMPHOMA

Background: Previous studies have shown associations between the risk of lymphoma and autoimmune diseases (AIDs). Mendelian randomization (MR) can estimate causal effects of a modifiable exposure on outcomes. Herein, we estimated causal effects of AID on lymphoma using MR and analyzed clinical signatures in patients of AID-associated lymphoma. Methods: A two-sample MR framework was conducted to estimate the causal effect of genetic liability for AID on lymphoma. We enrolled in patients with a history for at least one year of AID, who diagnosed with lymphoma at Shandong Provincial Hospital. For each lymphoma case, 1 lymphoma-free AID individual was identified as a control. Measures of relative risk were calculated using conditional logistic regression. Results: Strong evidence of a potential causal effect of AID on the risk of lymphoma was found (p = 0.040). Slopes of MR regressions and causal estimates associated with each SNP are illustrated (Figure 1). In the examination of the association between single autoimmune disease and lymphoma, the only potential causal effect of Sjögren syndrome (SS) was detected (p < 0.01). There was no heterogeneity, and these effects were robust to various MR assumptions. 55 cases of lymphoma were collected and matched to 110 controls randomly selected. The number of patients according to AID lymphoma subtypes were described using heatmap (Figure 2). The median age at AID was 60 years, and the median lymphoma-diagnosing age was 40 years. The clinical course from AID to lymphoma varies considerably, with a median time of 10 years. There was a female predominance (n = 29, 52.7%). Cases with a history of rheumatoid arthritis (RA) accounted for 32.73% (n = 18), followed by psoriasis (PsO) (n = 9). Baseline characteristics of patients and controls did not significantly differ in sex, age at AID onset, age of matching time or duration of AID. Cohorts as generated by the matching process were balanced. The most represented subtype was NHL (n = 45), of which 15 were DLBCL. Among those patients, 7 were GCB type and 1 was non-GCB type. According to incomplete IHC results, 23/28 patients expressed CD20. Ki67 index of 15 patients was greater than or equal to 60%. Median follow-up for surviving patients was 49.5 months. The 1-, 3-, and 5-year OS rates were 72.5%, 45%, and 22.5%, respectively. On univariate analysis, factors including sex, type of AID, age at AID/lymphoma and disease duration were not related to lymphoma risk. The assessment of ORs for the history of RA and PsO revealed no significantly increased risks for lymphoma (OR 1.027 for RA, 1.022 for PsO). Keyword: aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Bidirectional two-sample Mendelian randomization analysis reveals a causal effect of interleukin-18 levels on postherpetic neuralgia risk.

Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster, characterized by persistent neuropathic pain that significantly impairs patients' quality of life. Identifying factors that determine PHN susceptibility is crucial for its management. Interleukin-18 (IL-18), a pro-inflammatory cytokine implicated in chronic pain, may play a critical role in PHN development. In this study, we conducted bidirectional two-sample Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between IL-18 protein levels increasing and PHN risk, utilizing genome-wide association study (GWAS) datasets on these traits. Two IL-18 datasets obtained from the EMBL's European Bioinformatics Institute database which contained 21,758 individuals with 13,102,515 SNPs and Complete GWAS summary data on IL-18 protein levels which contained 3,394 individuals with 5,270,646 SNPs. The PHN dataset obtained from FinnGen biobank had 195,191 individuals with 16,380,406 SNPs. Our findings from two different datasets of IL-18 protein levels suggest a correlation between genetically predicted elevations in IL-18 protein levels and an increased susceptibility to PHN.(IVW, OR and 95% CI: 2.26, 1.07 to 4.78; p = 0.03 and 2.15, 1.10 to 4.19; p =0.03, respectively), potentially indicating a causal effect of IL-18 protein levels increasing on PHN risk. However, we did not detect any causal effect of genetic liability to PHN risk on IL-18 protein levels. These findings suggest new insights into identifying IL-18 protein levels increasing at risk of developing PHN and may aid in the development of novel prevention and treatment approaches for PHN.

Depression and 24 gastrointestinal diseases: a Mendelian randomization study

The causality of the association between depression and gastrointestinal diseases is undetermined. We conducted Mendelian randomization (MR) analyses to systematically explore the associations of depression with 24 gastrointestinal diseases. Independent genetic variants associated with depression at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analysis was conducted to explore the mediation effects of body mass index, cigarette smoking, and type 2 diabetes. After multiple-testing corrections, genetic liability to depression was associated with an increased risk of irritable bowel syndrome, non-alcohol fatty liver disease, alcoholic liver disease, gastroesophageal reflux, chronic pancreatitis, duodenal ulcer, chronic gastritis, gastric ulcer, diverticular disease, cholelithiasis, acute pancreatitis, and ulcerative colitis. For the causal effect of genetic liability to depression on non-alcoholic fatty liver disease, a substantial proportion was mediated by body mass index. Genetic predisposition to smoking initiation mediated half of effect of depression on acute pancreatitis. This MR study suggests that depression may play a causal role in many gastrointestinal diseases.

Genetic liability to mental disorders in relation to the risk of hypertension.

Observational studies have indicated that psychosocial factors contribute to hypertension; however, the causality of these associations remains unclear due to reverse causality and confounders. We aim to assess the causal associations of mental health disorders with hypertension. Instrumental variables of anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, depression, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, and subjective well-being measure were obtained from the corresponding largest genome-wide association studies. Summary statistics for the association of essential hypertension were obtained from the FinnGen Study (42,857 cases and 162,837 controls) and UK Biobank cohort (54,358 cases and 408,652 controls). The multiplicative random-effects inverse-variance weighted method was utilized as the primary analysis and three other statistical methods were conducted in the supplementary analyses. The results were combined using the fixed-effects method. In the pooled analyses, genetic liability to depression was associated with higher risk of hypertension (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17-1.35; p < 0.001). Besides, a suggestive association was found between genetically predicted higher weighted neuroticism sum-score and increased risk of hypertension (OR, 1.16; 95% CI, 1.02-1.33; p < 0.05). No associations were found for other mental health disorders. Sensitivity analyses revealed consistent evidence as the main results. We provide consistent evidence for the causal effect of genetic liability to depression on hypertension, which highlights the importance of blood pressure measurement and monitoring in patients with depression.

Parkinson's disease and the risk of gastrointestinal cancers: a two-sample Mendelian randomization study.

The association between Parkinson's disease (PD) and gastrointestinal (GI) cancers remains unknown. This study aims to assess the causal effect of PD on colon cancer (CC), gastric cancer (GC), esophageal cancer (EC), and rectal cancer (RC) using the two-sample Mendelian randomization (MR) method. Five pairs of summary datasets of genome-wide association studies (GWAS) from publicly available studies [Integrative Epidemiology Unit (IEU) OpenGWAS project, FinnGen, and GWAS Catalog database] were enrolled. The inverse variance weighted (IVW) method was used as the primary outcome for MR analysis. Cochran Q-derived, MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods, and leave-one-out analysis were used to test heterogeneity and directional pleiotropy. For the European population, no significant causal effect of PD on the risk of CC was found [odds ratio (OR) =0.9; 95%, confidence interval (CI): 1.00-1.11; P=0.42]. The same applied to the East Asian population (OR =1.05; 95% CI: 0.66-1.66; P=0.63). As for GC, no causal effect was found (OR =0.94, 95% CI: 0.89-0.99; P=0.22). Moreover, the genetic liability for PD was not associated with EC (OR =1.00; 95% CI: 0.99-1.00; P=0.32). Finally, no evidence was found for any causal effect of genetic liability for PD on an increased risk of RC (OR =1.00; 95% CI: 0.99-1.00; P=0.71). There is no causal effect of genetic liability for PD on an increased risk of GI cancer.

Genetic support of a causal relationship between cannabis use and educational attainment: a two-sample Mendelian randomization study of European ancestry.

Excessive cannabis use may lead to lower educational attainment. However, this association may be due to confounders and reverse causality. We tested the potential causal relationship between cannabis use disorder (CUD) or life-time cannabis use (LCU) and educational attainment. Bidirectional two-sample Mendelian randomization (MR) study was conducted. Our primary method was inverse-variance weighted (IVW) MR, with a series of sensitivity analyses. Multivariable MR (MVMR) was performed to estimate any direct effect independent of intelligence, smoking initiation or attention deficit hyperactivity disorder (ADHD). European ancestry individuals. The sample sizes of the genome-wide association study ranged from 55 374 to 632 802 participants. Genetic variants of CUD, LCU or educational attainment. Using univariable MR, we found evidence of a potential causal effect of genetic liability to CUD on a lower educational attainment [MR, 95% confidence interval (CI)inverse variance weighted (IVW) = -1.2month (-1.9month, -0.5month); P = 0.0008]. However, we found no evidence of an effect of genetic liability to LCU on educational attainment [MR, 95% CIIVW = 0.5month (-1.5month, 2.6month), P = 0.6032]. Reverse direction analysis suggested that genetic liability to higher educational attainment had a potential causal effect on lower risk of CUD [odds ratio (OR), 95% CIIVW = 0.39 (0.29, 0.52), P = 1.69 × 10-10 ]. We also found evidence of potential causal effect from genetic liability to higher educational attainment to higher risk of LCU [OR, 95% CIIVW = 1.35 (1.11, 1.66), P = 0.0033]. Genetic liability to cannabis use disorder may lead to lower educational attainment. Genetic liability to higher educational attainment may also lead to higher life-time cannabis use risk and lower cannabis use disorder risk. However, the bidirectional effect between cannabis use disorder and educational attainment may be due to shared risk factors (e.g. attention-deficit hyperactivity disorder).

Mendelian Randomization Analyses of the Impact of Autoimmune Disease on Lymphoma

Background: Autoimmune diseases (AIDs) are a heterogeneous group of disorders caused by abnormal immune responses. Results from previous investigations have shown associations between the risk of lymphoma and a history of autoimmune diseases. However, it is unknown if this association is causal or confounded. Mendelian randomization (MR) is a genetic epidemiology method using genetic variants as predictors to estimate causal effects of a modifiable exposure on an outcome. Herein, we estimated the causal effect of AID on lymphoma in a general European population using MR. Methods: A two-sample MR framework was conducted to estimate the causal effect of genetic liability for AID on lymphoma. A random-effects (IVW) method was used for the MR estimation, which allowed the instruments to be invalid if the horizontal pleiotropy was balanced on the whole. Lymphoma risk estimates were presented as odds ratios (OR) with 95% confidence (95% CI) intervals per unit increase in log odds of AID. Statistical analysis was conducted using Two-sample MR R package. Results:The Genome-wide association studies (GWAS) data for lymphoma (1,752 cases with lymphoma and 359,442 control samples) were analyzed. The GWAS summary statistics of AID and diseases including RA, SLE, psoriasis (PsO), sjögren syndrome (SS), ankylosing spondylitis (AS), and systemic sclerosis (SSc) were obtained from a recent published GWAS, with 42,202 European AID cases and 176,590 control cases. Using 36 AID-related SNPs, strong evidence of a potential causal effect of AID on the risk of lymphoma was found (OR = 1.001, 95% CI = 1.000-1.002, p = 0.040). Meanwhile, similar risk estimates were gained using the MR-Egger regression (OR = 1.002, 95% CI = 1.000-1.003, p = 0.018) and weighted median approaches (OR = 1.001, 95% CI = 1.000-1.002, p=0.152). Heterogeneity was observed with a Cochran Q-test derived p value as 0.002 of MR-Egger and p value as 0.001 of IVW, which could be ignored for the consistence of the MR estimates. Slopes of MR regressions and causal estimates associated with each SNP are illustrated. In addition, according to the leave-one-out sensitivity analysis, no single SNP strongly disrupted the overall effect of AID on lymphoma. No unbalanced horizontal pleiotropy or evident heterogeneity was found. We further explored the association between single autoimmune disease and lymphoma. In the MR analysis, the only potential causal effect of SS on risks of lymphoma was detected (OR = 1.002, 95%CI = 1.001-1.002,p < 0.01). The same direction of association was obtained using other MR estimators. A Cochran Q-test derived p value was 0.056 of IVW and 0.063 of MR-Egger, indicating no heterogeneity. Additional sensitivity analyses suggested that these effects were robust to various MR assumptions. Conclusions:Our study is the first to report the potential causality of AID on lymphoma through MR analysis. In addition, a strong relationship between SS and risk of lymphoma was found. Therefore, for patients with autoimmune diseases, long-term and close follow-up is required to be alert to the occurrence of lymphoma. Disclosures: No relevant conflicts of interest to declare. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

Few studies suggest possible links between attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and Alzheimer’s disease but they have been limited by small sample sizes, diagnostic and recall bias. We used two-sample Mendelian randomization (MR) to estimate the bidirectional causal association between genetic liability to ADHD and ASD on Alzheimer’s disease. In addition, we estimated the causal effects independently of educational attainment and IQ, through multivariable Mendelian randomization (MVMR). We employed genetic variants associated with ADHD (20,183 cases/35,191 controls), ASD (18,381 cases/27,969 controls), Alzheimer’s disease (71,880 cases/383,378 controls), educational attainment (n = 766,345) and IQ (n = 269,867) using the largest GWAS of European ancestry. There was limited evidence to suggest a causal effect of genetic liability to ADHD (odds ratio [OR] = 1.00, 95% CI: 0.98–1.02, P = 0.39) or ASD (OR = 0.99, 95% CI: 0.97–1.01, P = 0.70) on Alzheimer’s disease. Similar causal effect estimates were identified as direct effects, independent of educational attainment (ADHD: OR = 1.00, 95% CI: 0.99–1.01, P = 0.76; ASD: OR = 0.99, 95% CI: 0.98–1.00, P = 0.28) and IQ (ADHD: OR = 1.00, 95% CI: 0.99–1.02. P = 0.29; ASD: OR = 0.99, 95% CI: 0.98–1.01, P = 0.99). Genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR = 1.12, 95% CI: 0.86–1.44, P = 0.37; ASD: OR = 1.19, 95% CI: 0.94–1.51, P = 0.14). We found limited evidence to suggest a causal effect of genetic liability to ADHD or ASD on Alzheimer’s disease; and vice versa.

Causal effect of COVID-19 on Alzheimer's disease: A Mendelian randomization study.

It was reported that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection may cause brain size reduction and cognitive decline. Whether COVID‐19 may contribute to the development of Alzheimer's disease (AD) is not known. We conducted genetic correlation and Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between AD and three COVID‐19 outcomes (SARS‐CoV‐2 infection, COVID‐19 hospitalization, and critical COVID‐19) by utilizing genome‐wide association study datasets on these traits. A map of COVID‐19‐driven molecular pathways was constructed to investigate potential mechanisms underlying the COVID‐19 and AD connection. Genetic correlation analyses indicated that AD had a significant positive genetic correlation with hospitalized COVID‐19 (r g = 0.271). The MR analysis from the inverse‐variance‐weighted model showed that genetic liabilities to hospitalized COVID‐19 (odds ratio: 1.02, 95% confidence interval: 1.01–1.03) and critical COVID‐19 (1.01, 1.00–1.02) were associated with an increased risk for AD. However, no causal effect of genetic liability to SARS‐CoV‐2 infection on AD was detected (1.03, 0.97–1.09). A total of 60 functionally interconnected genes were reported to mediate the COVID‐19‐AD connection, which showed functional enrichment in immunity‐related pathways and tissue enrichment in the lung and brain. Our study suggests that severe COVID‐19 may contribute to the development of AD, while suffering a mild case of COVID‐19 may not increase the risk for AD. The influence of COVID‐19 on AD may be mediated by immunity‐related pathways acting predominantly in the lung and brain.

Parental inflammatory bowel disease and autism in children

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.

Genetic liability for prescription opioid use and risk of cardiovascular diseases: a multivariable Mendelian randomization study.

Observational studies have yielded conflicting results on the association of prescription opioid use (POU) with the risk of cardiovascular diseases (CVD). Residual confounding and potential reverse causality are inevitable in such conventional observational studies. This study used Mendelian randomization (MR) design to estimate the causal effect of POU on the risk of CVD, including coronary heart disease (CHD), myocardial infarction (MI) and ischemic stroke (IS), as well as their common risk factors. We estimated the causal effect of genetic liability for POU on CVD in a two-sample MR framework. Complementary sensitivity analyses were conducted to test the robustness of our results. Genome-wide association studies (GWAS) that were based on predominantly European ancestry. The sample sizes of the GWAS used in this study ranged from 69 033 to 757 601 participants. Genetic variants predictive of the POU and their corresponding summary-level information in the outcomes were retrieved and extracted from the respective GWAS. Using univariable MR, we found evidence for a causal effect of genetic liability for POU on an increased risk of CHD [odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.02-1.16; P = 0.008] and MI (OR = 1.13; 95% CI = 1.04-1.22; P = 0.002). In multivariable MR, the association remained after accounting for comorbid pain conditions, but was attenuated with adjustment for potential mediators, including body mass index (BMI), waist circumference (WC) and type 2 diabetes (T2D). Mendelian randomization estimates provide robust evidence for the causal effects of genetic liability for prescription opioid use on an increased risk of coronary heart disease and myocardial infarction, which might be mediated by obesity-related traits.

Type 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression.

Background:Type 2 diabetes (T2DM) and Parkinson’s disease (PD) are prevalent diseases that affect an aging population. Previous systematic reviews and meta-analyses have explored the relationship between diabetes and the risk of PD, but the results have been conflicting.Objective:The objective was to investigate T2DM as a determinant of PD through a meta-analysis of observational and genetic summary data.Methods:A systematic review and meta-analysis of observational studies was undertaken by searching 6 databases. We selected the highest-quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate the causal effects of genetic liability toward T2DM on PD risk and progression, using summary data derived from genome-wide association studies.Results:In the observational part of the study, pooled effect estimates showed that T2DM was associated with an increased risk of PD (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07–1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (standardized mean difference [SMD] 0.55, 95% CI 0.39–0.72) and cognitive decline (SMD −0.92, 95% CI −1.50 to −0.34). Using MR, we found supportive evidence for a causal effect of diabetes on PD risk (inverse-variance weighted method [IVW] OR 1.08, 95% CI 1.02–1.14; P = 0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01–1.20; P = 0.032) but not on cognitive progression.Conclusions:Using meta-analyses of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk and new evidence to support a role in PD progression.