Genome-wide Association Studies Summary Research Articles

Causal relationship between depression and hypercholesterolemia: A bidirectional 2-sample Mendelian randomization study.

Although observational studies have found both a positive and negative association between depression and hypercholesterolemia, the findings are mixed and contradictory. To our knowledge, this is the first study that employs the bidirectional Mendelian randomization (MR) and multivariable MR analysis with extensive genome-wide association studies (GWAS) data to examine the causal effect between depression and hypercholesterolemia. Using summary statistics obtained from GWAS of individuals with European ancestry, we utilize a bidirectional 2-sample MR approach to explore the potential causal association between hypercholesterolemia and depressive symptoms. Multivariable Mendelian randomization analysis was used to examine whether the direct causal effect of depression on the risk of hypercholesterolemia can be affected by traits associated with the increased risk of hypercholesterolemia. This MR analysis utilized inverse variance weighted (IVW), MR-Egger regression, weighted mode, and weighted median methods. Data on the summary level of depression were acquired from a GWAS that involved 500,199 participants. We used summary GWAS datasets for hypercholesterolemia including 206,067 participants. We also used another GWAS databases of hypercholesterolemiat (n = 463,010) to validate our results. By utilizing IVW, it was discovered that there is a possibility of a 31% rise in the risk of hypercholesterolemia due to depression (OR = 1.31, 95% CI = 1.10-1.57, P = .002). We found a consistent causal effect of depression on hypercholesterolemia from the IVW analyses using different hypercholesterolemia datasets. After adjustment of smoking, physical activity, and obesity, there remains significant causal relationship between depression and hypercholesterolemia (OR = 1.25, 95% CI = 1.01-1.54, P = .040). However, we did not find any evidence indicating that hypercholesterolemia leads to depression in the opposite direction. Directional pleiotropy was not observed in the MR-Egger regression analysis. Additionally, the MR-PRESSO analysis validated these discoveries. Neither the leave-one-out sensitivity test nor the funnel plots revealed any outliers. In both the unadjusted and adjusted estimates, depression has a consistent direct causal effect on hypercholesterolemia. Our study has led to an improved comprehension of the causal connections between hypercholesterolemia and depression, which could aid in the prevention and treatment of hypercholesterolemia.

Genetic liability to inflammatory bowel disease is causally associated with increased risk of erectile dysfunction: Evidence from a bidirectional Mendelian randomization study.

Background: Several observational cohort studies suggested a close correlation between inflammatory bowel disease and erectile dysfunction. Nevertheless, whether there was a causal effect between them remained debatable. In this study, we aimed to detect the underlying causal links between genetically predicted inflammatory bowel disease and the risk of erectile dysfunction. Methods: A bidirectional Mendelian randomization (MR) study was performed to assess the causal link between inflammatory bowel disease and erectile dysfunction. Inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode were utilized to estimate the causality. The top single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease cases (n = 25,800) and erectile dysfunction cases (n = 1,154) were extracted from the summary genome-wide association study (GWAS) data obtained from a publicly attainable database. MR-PRESSO global outlier test and MR-Egger regression were utilized to explore the horizontal pleiotropy and outlier instrumental variables. Cochran's Q statistic was utilized to detect the heterogeneity. Results: In the forward MR study, the IVW approach demonstrated that genetically determined inflammatory bowel disease exhibited a suggestively causal association with an increased risk of erectile dysfunction (OR: 1.11, 95% CI: 1.02-1.21, p = 0.019), and also the genetically determined Crohn's disease was found to be causally associated with an increased risk of erectile dysfunction (OR: 1.09, 95% CI: 1.02-1.17, p = 0.014). However, the MR analysis results showed no significant evidence supporting a causal effect of ulcerative colitis with erectile dysfunction (OR: 1.02, 95% CI: 0.92-1.14, p = 0.679). Furthermore, the reverse MR analysis showed no causal effects of genetically determined erectile dysfunction on inflammatory bowel disease. Additionally, sensitivity analysis demonstrated no pleiotropy and heterogeneity. Conclusion: Our MR analysis substantiated causal links of inflammatory bowel disease and Crohn's disease on erectile dysfunction, which may further elucidate how inflammatory bowel disease impacted the initiation and development of erectile dysfunction, and facilitated the prevention and clinical management of inflammatory bowel disease in individuals with erectile dysfunction.

Hypothyroidism's effect on stroke limited to specific subtypes: A Mendelian randomization study

BackgroundThe association between hypothyroidism and stroke remains controversial and the association between hypothyroidism and stroke subtypes has not been satisfactorily researched. This study aimed to explore the causal effect of hypothyroidism on the risk of stroke and its subtypes by Mendelian randomization (MR) analysis. MethodsSingle nucleotide polymorphisms (SNPs) were selected from published genome-wide association studies (GWAS) meta-analysis as instrumental variables (IVs) for hypothyroidism. As outcomes, summary GWAS data for stroke and its subtypes were obtained from two other large GWAS meta-analyses, including any stroke (AS), any ischemic stroke (AIS), large vessel stroke (LAS), cardiogenic embolic stroke (CES), small vessel stroke (SVS), and intracranial hemorrhage (ICH). Univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR) were used to assess the causal effect of hypothyroidism on stroke and its subtypes. ResultsIn UVMR, genetically predicted hypothyroidism was significantly associated with LAS (OR = 1.14, 95CI = 1.02-1.27) and SVS (OR = 1.14, 95CI = 1.04-1.25), but not with AS, AIS, CES, and ICH. The results of the MVMR showed that after adjusting for smoking, alcohol consumption, hypertension, diabetes, low-density lipoprotein cholesterol (LDL-c), and body mass index (BMI), the causal association between hypothyroidism and SVS remained significant, while the association between hypothyroidism and LAS became nonsignificant. ConclusionHypothyroidism is causally associated with risk for LAS and SVS, but not for other stroke subtypes. Hypothyroidism may be an independent risk factor for SVS, and vascular risk factors play an important role in hypothyroidism causing LAS.

Mapping the causal associations of cytokines with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization.

Cytokines and growth factors may serve as a bridge in studying the causal relationships between inflammaging and sarcopenia due to their roles in inflammaging. In this study, we aim to explore the causal association of cytokines with sarcopenia and aging traits and further identify the significant inflammation factors. Bidirectional Mendelian randomization (MR) analysis was used to identify the causality. Forty-one kinds of circulation cytokines and growth factors were set as exposures, and the data were from a summary genome-wide association study (GWAS) containing three cohorts with 8293 healthy participants of European ancestry from 1983 to 2011. Hand grip strength, adjusted appendicular lean mass (AALM), usual walking pace, moderate-to-vigorous physical activity (MVPA) levels, able to walk or cycle unaided for 10min (AWCU10) and telomere length were selected as outcomes. Data for outcomes were obtained from meta-GWAS and the UK Biobank, and sample sizes ranged from 69537 to 472174. Low hand grip strength was defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and Foundation for the National Institutes of Health (FNIH) cut-off points, respectively. Other outcome traits were defined and measured according to the UK Biobank and raw cohorts' criteria. We set two significance thresholds for single nucleotide polymorphisms (SNPs) associated with exposures to obtain adequate SNPs (5×10-6 and 5×10-8). Inverse-variance weighted, MR-Egger and weighted median were employed to estimate the causality. Twenty-seven factors were identified to relate to sarcopenia and aging traits causally, and most were associated with only one outcome trait. IL16 (interleukin-16), CTACK (cutaneous T-cell attracting chemokine), MIP1b (macrophage inflammatory protein 1b) and PDGFbb (platelet-derived growth factor BB) were proven to relate causally to at least one sarcopenia and aging trait in both analyses with two significance thresholds. IL16 was causally associated with hand grip strength (0.977 [0.956-0.998] for EWGSOP and 0.933 [0.874-0.996] for FNIH), AALM (0.991 [0.984, 0.998]), MVPA (0.997 [0.995-1.000]) and AWCU10 (1.008 [1.003-1.013]). CTACK was proven to relate causally to hand grip strength (1.013 [1.007-1.019] for EWGSOP and 1.090 [1.041-1.142] for FNIH), AWCU10 (0.990 [0.986-0.994]) and telomere length (0.998 [0.983-0.994]). The results indicated that MIP1b has a causal effect on hand grip strength (1.032 [1.001-1.063] for EWGSOP), AWCU10 (0.994 [0.988-1.000] and 0.993 [0.988-0.998]) and telomere length (1.006 [1.000-1.012]). PDGFbb may causally relate to AALM (1.016 [1.001-1.030]) and telomere length (1.011 [1.007-1.015]). Reserve MR analyses also proved their unidirectional causal effects. Twenty-seven factors were causally related to sarcopenia and aging traits, and the causal effects of IL16, CTACK, MIP1b and PDGFbb were proven in both analyses with two significance thresholds.

Association between inflammatory bowel disease and cancer risk: evidence triangulation from genetic correlation, Mendelian randomization, and colocalization analyses across East Asian and European populations

BackgroundInflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have been inconsistent and may face the bias of confounding and reverse causality. The potential causal relationships between IBD and the risk of cancers remain largely unclear.MethodsWe performed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analyses using summary genome-wide association study (GWAS) data across East Asian and European populations to evaluate the causal relationships between IBD and cancers. Sensitivity analyses for the MR approach were additionally performed to explore the stability of the results.ResultsThere were no significant genetic correlations between IBD, CD, or UC and cancers (all P values > 0.05) in East Asian or European populations. According to the main MR analysis, no significant causal relationship was observed between IBD and cancers in the East Asian population. There were significant associations between CD and ovarian cancer (odds ratio [OR] = 0.898, 95% CI = 0.844–0.955) and between UC and nonmelanoma skin cancer (OR = 1.002, 95% CI = 1.000–1.004, P = 0.019) in the European population. The multivariable MR analysis did not find any of the above significant associations. There was no shared causal variant to prove the associations of IBD, CD, or UC with cancers in East Asian or European populations using colocalization analysis.ConclusionsWe did not provide robust genetic evidence of causal associations between IBD and cancer risk. Exposure to IBD might not independently contribute to the risk of cancers, and the increased risk of cancers observed in observational studies might be attributed to factors accompanying the diagnosis of IBD.

Dissecting the causal relationship between neuroticism and osteoarthritis: a univariable and multivariable Mendelian randomization study.

Mental health has been found to be associated with risk of osteoarthritis (OA), but the causal relationship was not fully clarified. Two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between neuroticism (n = 329,821) and the two most frequently affected parts of osteoarthritis (OA) (knee OA: case/control =24,955/378,169; hip OA: case/control = 15,704/378,169) using large scale summary genome-wide association study (GWAS) data. Inverse variance weighted (IVW), weighted median, and MR-Egger were used to estimate the causal effects. Multiple sensitivity analyses were conducted to examine the robustness of the causal estimates. Multivariable MR analysis was used to estimate the direct effects of neuroticism on OA after accounting for the other OA risk factors. Two-step MR approach was employed to explore the potential mediators of the causal relationship. Univariable MR analysis indicated that 1-SD increase in genetically predicted neuroticism score was associated with an increased risk of knee OA (IVW: OR, 1.17; 95% CI, 1.087-1.26; p = 2.72E-05) but not with hip OA. The causal effects remained significant after accounting for the effects of BMI, alcohol drinking, and vigorous physical activity but were attenuated with adjustment of smoking. Further mediation analysis revealed that smoking initiation mediated a significant proportion of the causal effects of neuroticism on knee OA (proportion of mediation effects in total effects: 22.3%; 95% CI, 5.9%-38.6%; p = 7.60E-03). Neuroticism has significant causal effects on knee OA risk. Smoking might partly mediate the causal relationship. Further studies were warranted to explore the underlying mechanisms and potential use of neuroticism management for OA treatment.

Potential causal associations between leisure sedentary behaviors, physical activity, sleep traits, and myopia: a Mendelian randomization study

BackgroundMyopia is the most prevalent refractive error and a growing global health concern that significantly affects visual function. Researchers have recently emphasized considerably on the influence of lifestyle on myopia incidence and development. This study investigates the relationship between leisure sedentary behaviors (LSB)/physical activity (PA)/sleep traits and myopia.MethodsLSB, PA, and sleep trait-associated genetic variants were used as instrument variables in a Mendelian randomization (MR) study to examine their causal effects on myopia. Summary genome-wide association studies (GWASs) statistical data for LSB and PA were obtained from UK Biobank, and the data of sleep traits was obtained from UK Biobank, UK Biobank and 23andMe, and FinnGen. We used summary statistics data for myopia from MRC IEU. The MR analyses was performed using the inverse variance-weighted (IVW), MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier methods.ResultsComputer use was genetically predicted to increase the myopia risk [IVW odds ratio (OR) = 1.057; 95% confidence interval (CI), 1.038–1.078; P = 7.04 × 10− 9]. The self-reported moderate-to-vigorous physical activity (MVPA) (IVW OR = 0.962; 95% CI, 0.932–0.993; P = 1.57 × 10− 2) and television watching (IVW OR = 0.973; 95% CI, 0.961–0.985, P = 1.93 × 10− 5) were significantly associated with a lower myopia risk. However, genetically predicted sleep traits or accelerometer-measured physical activity had no significant associations with myopia.ConclusionOur results indicated that computer use is a risk factor for myopia, whereas television watching and MVPA may protect against myopia. These findings shed new light on possible strategies for reducing the prevalence of myopia.

Assessing the Causal Relationship between Genetically Determined Inflammatory Cytokines and Parkinson's Disease Risk: A Bidirectional Two-Sample Mendelian Randomization Study.

Observational studies have suggested an association between inflammatory cytokines and Parkinson's disease (PD). This Mendelian randomization (MR) was conducted to further assess the causal correlations between inflammatory cytokines and PD. Genetic instruments associated with inflammatory cytokines were extracted from a large summary genome-wide association studies (GWAS) involving 8,293 European participants. Summary-level statistics for PD were obtained from a large-sample GWAS containing 17 studies that involved European participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted (IVW) method. The IVW method indicated that basic fibroblast growth factor (FGFBasic), interleukin-2 (IL-2), and macrophage migration inhibitory factor (MIF) may be suggestively associated with the risk of PD (OR: 0.71, 95%CI: 0.52-0.96, P = 0.027; OR: 1.18, 95%CI: 1.01-1.38, P = 0.041; and OR: 1.23, 95%CI: 1.04-1.46, P = 0.018). In the reverse direction, monokine induced by interferon gamma (MIG), beta nerve growth factor (bNGF), interleukin-17 (IL-17), and interferon gamma (IFNg) are suggested to be the consequences of PD. Our MR analysis indicated that suggestive associations between circulating levels of FGFBasic, IL-2, and MIF and PD risk. In addition, MIG, bNGF, IL-17, and IFNg are more likely to be involved in the development of downstream PD.

No evidence of a causal relationship between miscarriage and 25-hydroxyvitamin D: a Mendelian randomization study.

Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage? In this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages. Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear. The latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417580), vitamin D deficiency (426 cases and 354812 controls), miscarriage (16906 cases and 149622 controls), and the number of miscarriages (n = 78700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis. This study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively. There was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P = 0.927), or the number of miscarriages (β = -0.004, 95% CI: -0.040 to 0.032, P = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P = 0.624), or the number of miscarriages (β = 0.001, 95% CI: -0.009 to 0.011, P = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found. This study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups. These findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage. This project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare. N/A.

Gamma-glutamyl transferase and calculus of kidney incidence: a Mendelian randomization study

Elevated Gamma-glutamyl transferase (GGT) levels are often suggestive of cholelithiasis, and previous studies have indicated that GGT is highly expressed in the urinary system. Therefore, we hypothesized that there may be an association between GGT levels and calculus of kidney (CK) incidence. To investigate this potential causal relationship, we employed Mendelian randomization (MR) analysis. Additionally, we analyzed the levels of other liver enzymes, including alanine transaminase (ALT) and alkaline phosphatase (ALP). The relationship between GGT levels and CK incidence was analyzed using two-sample Mendelian randomization. Summary Genome-Wide Association Studies data were utilized for this analysis. 33 single nucleotide polymorphisms known to be associated with GGT levels were employed as instrumental variables. We employed several MR methods including IVW (inverse variance weighting), MR-Egger, weighted median, weighted mode, and MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier). Furthermore, we conducted tests for horizontal multivariate validity, heterogeneity, and performed leave-one-out analysis to ensure the stability of the results. Overall, several MR methods yielded statistically significant results with a p-value < 0.05. The results from the IVW analysis yielded an odds ratio (OR) of 1.0062 with a 95% confidence interval (CI) of 1.0016–1.0109 (p = 0.0077). Additional MR methods provided supplementary results: MR-Egger (OR 1.0167, 95% CI 1.0070–1.0266, p = 0.0040); weighted median (OR 1.0058, 95% CI 1.0002–1.0115, p = 0.0423); and weighted mode (OR 1.0083, 95% CI 1.0020–1.0146, p- = 0.0188). Sensitivity analyses did not reveal heterogeneity or outliers. Although potential horizontal pleiotropy emerged, we speculate that this could be attributed to inadequate test efficacy. However, subsequent use of MR-PRESSO did not provide evidence of pleiotropy. Our analysis suggests a positive association between elevated GGT levels and CK incidence, indicating an increased risk of CK development. However, no causal relationship was observed between levels of ALP or ALT and CK incidence.

Causal Association between Tea Intake and Acute Cerebrovascular Events: A Multivariate Mendelian Randomized Study in European Populations

BackgroundNumerous research works have investigated the association between tea consumption and the risk of acute cerebrovascular events; however, the results are inconsistent. ObjectivesWe used Mendelian randomization (MR) to evaluate the causal association between tea intake and several acute cerebrovascular events, including any ischemic stroke, large atherosclerotic stroke (LAS), cardiogenic embolic stroke (CES), small vessel stroke (SVS), intracranial hemorrhage (ICH), and subarachnoid hemorrhage (SAH). MethodsWe obtained summary genome-wide association study (GWAS) data on tea intake and acute cerebrovascular events in populations of European ancestry. The GWAS on tea intake is derived from the UK Biobank, where we have chosen single-nucleotide polymorphisms (SNPs) closely associated with it as instrumental variables. We also obtained summary data on ischemic stroke from a GWAS meta-analysis, as well as summary data on ICH and SAH from the FinnGen study. We first explored the causal association between tea intake and several acute cerebrovascular events using univariate Mendelian randomization (UVMR), and then further assessed the causal association between tea intake and SVS using multivariate Mendelian randomization (MVMR) corrected for multiple confounders. ResultsIn UVMR, genetically predicted increases in tea intake were linked to a lower risk of SVS (OR: 0.58; 95% CI: 0.39, 0.86). There was no causal association between tea intake and the risk of other acute cerebrovascular events. In the MVMR, our results show that there was still a significant causal association between drinking tea and SVS, after adjusting body mass index, total cholesterol, low-density lipoprotein cholesterol, diabetes, hypertension, smoking, and alcohol consumption. ConclusionThis MR study provides new genetic evidence that increased tea intake reduces the risk of SVS in the European population. However, possibly because of limited statistical power, the study did not find that tea consumption reduced the risk of several other acute cerebrovascular events.

Lifestyle habits and gastric cancer in an East Asian population: a Mendelian randomization study.

Epidemiological evidence suggests an association between lifestyle habits (smoking, alcohol consumption, tea, coffee intake, etc.) and gastric cancer (GC). However, the causal relationship remains uncertain. Therefore, the purpose of this study was to ascertain whether there is a causal connection between them. Two-sample Mendelian randomization (MR) analysis was performed using the publicly available Genome Wide Association Study summary datasets using six methods: inverse variance weighting (IVW), weighted median, MR using a Robust Adjusted Profile Score (MR.Raps), MR using a Robust Adjusted Profile Score (MR-PRESSO), Radial regression of MR, and Causal Analysis Using Summary Effect Estimates (CAUSE). A sensitivity analysis was conducted to assess the robustness of the results. In an East Asian population, we found that increased tea intake reduced the risk of GC [odds ratio (OR)= 0.90, 95% confidence interval (CI)= 0.82-0.99, P = 0.037] while there was a positive association between smoking and GC (OR = 1.58, 95% CI = 1.04-2.39, P = 0.032). No causal relationship between alcohol and coffee intake and GC. Sensitivity analyses demonstrated the robustness of these causal associations. Our study suggests that tea intake may reduce the risk of GC, for which smoking is a potential risk factor. Nevertheless, a larger and more diverse sample size is needed for further validation.

Association of Kallikrein Related Peptidase 3 (KLK3) gene with dermatophytosis in the UK biobank cohort.

In a previous genome wide association study (GWAS) of UK Biobank (UKB) data, we identified one susceptibility locus, tubulointerstitial nephritis antigen (TINAG), with genome wide significance for dermatophytosis. We used genotype calls from file UKB22418. These data are derived directly from Affymetrix DNA microarrays but are missing many genotype calls. Using computationally efficient approaches, UKB has entered imputed genotypes into a second dataset, UKB22828, increasing the number of testable variants by over 100-fold to 96 million variants. In the current study, we used UKB imputed genotypes in UKB22828 to identify dermatophytosis susceptibility loci. To identify cases of dermatophytosis, we used ICD10 code B35, which covers tinea barbae, tinea capitis, tinea unguium, tinea manuum, tinea pedis, tinea corporis, tinea imbricata, tinea cruris, other dermatophytoses and dermatophytosis, unspecified. We used PLINK, a whole-genome association analysis toolset, to analyse the UKB22828 chromosome files. GWAS summary (Manhattan) plot of the meta-analysis association statistics highlighted two susceptibility loci, TINAG and Kallikrein Related Peptidase 3 (KLK3), with genome wide significance for dermatophytosis. KLK3, also known as prostate specific antigen (PSA), belongs to a subclass of serine proteases with a variety of physiological functions. KLK3 may be a dermatophytosis susceptibility gene. KLK3 could affect risk of dermatophytosis, since kallikreins are necessary for normal homeostasis of the skin.

Inflammatory biomarkers and delirium: a Mendelian randomization study.

The association between inflammatory biomarkers and individual delirium symptoms remains controversial in observational studies. We investigated the relationship between inflammatory biomarkers and the risk of developing delirium. A bidirectional two-sample Mendelian randomization (MR) was performed. Genetic instruments associated with peripheral tumor necrosis factor-a (TNF-a) C-reactive protein (CRP), interleukin (IL)-1α, IL-1β, IL-2, IL-8, IL-6, soluble IL-6 receptor alpha (sIL-6Rα), and soluble gp130 were identified in three different large summary genome-wide association studies (GWAS) conducted in the European population. Summary-level statistics for delirium not induced by alcohol and other psychoactive substances were obtained from the FinnGen consortium (2,612 cases and 325,306 controls). The estimated causal effects were performed using instruments' variants at the genome-wide significant level (P < 5e-8 and P < 5e-6), applying a linkage disequilibrium clumping approach with a threshold of r2 < 0.001 for each of the exposures. Reverse causation was also performed. The inverse-variance weighted method (IVW), MR-Egger method, weighted median method, MR-Egger regression, and MR Pleiotropy RESidual Sum were used for MR analyses. At the genome-wide significant level (P < 5e-8, r2 < 0.001), genetically predicted sIL-6Rα was significantly associated with a decreased risk of delirium with less than three single-nucleotide polymorphisms (SNPs) in all three GWAS data sources (ORWaldratio = 0.89, 95% CI: 0.79-0.96, PWaldratio = 0.0016; ORIVW = 0.88, 95% CI: 0.79-0.97, PIVW = 0.008; ORIVW = 0.88, 95% CI: 0.80-0.96, PIVW = 0.004). The causal relationship between sIL-6Rα and delirium became non-significant when a more liberal threshold of P of < 5e-6 was applied (all PIVW > 0.05). At the two genome-wide significance levels (P < 5e-8 and P < 5e-6), we found no evidence for the causal effects of peripheral TNF-α, CRP, IL-1α, IL-1β, IL-2, IL-6, IL-8, and soluble gp130 on delirium (all P > 0.05). The MR-Egger intercept and MR-PRESSO results indicated that no SNP had possible pleiotropy (all P > 0.05). Regarding the reverse, no evidence for an effect of delirium on these inflammatory biomarkers could be found (all P > 0.05). The results of this MR analysis did not support that peripheral TNF-α, CRP, IL-1α, IL-1β, IL-2, IL-6, sIL-6Rα, soluble gp130, and IL-8 were causally associated with delirium. More research is needed to explore the role of inflammatory factors in the pathogenesis of delirium.

#6774 CAUSAL ASSOCIATION OF COVID-19 AND KIDNEY FUNCTION: A MENDELIAN RANDOMIZATION ANALYSIS

Abstract Background and Aims Previous observational studies suggest that there are potential relationships between COVID-19 and kidney functions. However, whether COVID-19 had causal effects on different kidney traits is currently unclear. We aimed to investigate the causal link between genetically determined COVID-19 and following kidney traits. Method We performed univariate Mendelian randomization (MR) studies using summary genome-wide association studies (GWAS) statistics of COVID-19 severity (n case/n control: 13,769/1,072,442 for European, n case/n control: 794/4862 for Asian), COVID-19 hospitalization (n case/n control: 32,519/2,062,805 for European, n case/n control:2882/31,200 for Asian) and COVID-19 susceptibility (n case/n control: 122,616/2,475,240 for European, n case/n control: 4459/36,121 for Asian) derived from THE COVID-19 Host Genetics Initiative (r7) as exposure. Phenotypic outcomes analyzed for Europeans included chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate, Cystatin C-based estimated glomerular filtration rate, Urine albumin-to-creatinine ratio, acute and chronic glomerulonephritis, membranous nephropathy, diabetic nephropathy, acute and chronic nephritic syndrome, acute renal failure, glomerular diseases and IgA nephropathy. While for Asians, outcomes including CKD, estimated glomerular filtration rate, serum creatinine, acute and chronic renal failure, diabetic nephropathy, IgA nephropathy, nephrotic syndrome, acute and chronic glomerulonephritis as well as membranous nephropathy were analyzed. The inverse variance weighted (IVW) MR with multiplicative random effects model was performed as primary analysis to evaluate the causal effects of COVID-19 on different kidney traits, and potential pleiotropy as well as heterogeneity was evaluated by using MR Egger and heterogeneity test, respectively. A series of sensitivity analyses, including weighted median MR, weighted mode MR, MR Pleiotropy Residual Sum and Outlier (MR PRESSO) were performed. In addition, the causal effects of COVID-19 on different kidney traits were validated by using additional GWAS summary data of critical COVID-19 (n case/n control: 5989/42891 for European, n case/n control: 274/366 for Asian) from GenOMICC database (r6) as exposure. After multiple corrections, a P value &amp;lt; 0.0036 for Europeans and P value &amp;lt; 0.0045 for Asians were considered as significant. Results IVW MR indicated that none of the COVID-19 phenotypes were associated with CKD (OR, 0.99: P = 0.16 for COVID-19 severity; OR, 0.99: P = 0.41 for COVID-19 hospitalization; OR, 0.95: P = 0.26 for COVID-19 susceptibility), nor other kidney traits for Europeans. As for Asian ancestry, consistent with the findings in Europeans, none of the COVID-19 phenotypes were associated with CKD (OR, 0.89: P = 0.16 for COVID-19 severity; OR, 0.93: P = 0.42 for COVID-19 hospitalization; OR, 0.95: P = 0.61 for COVID-19 susceptibility), nor other kidney traits as mentioned above. All sensitivity analyses also consistently indicated the absence of causal effects of COVID-19 severity, hospitalization and susceptibility on different kidney traits, neither in the European nor in the Asian population. Conclusion There is no significant evidence supporting the causal effects of genetically predicted COVID-19 phenotype on the following different kidney traits. More deeply explorations focused on the association between COVID-19 and kidney traits should be performed with more data would be available in the future.

Causal associations between human gut microbiota and cholelithiasis: a mendelian randomization study.

There was some evidence that gut microbiota was closely related to cholelithiasis, but the causal relationship between them remained unclear. In this study, we try to use Two-sample Mendelian randomization (MR) to clarify the potential causal relationship between gut microbiota and cholelithiasis. Summary Genome-Wide Association Studies (GWAS) statistical data for gut microbiota was obtained from MiBioGen, and the data of cholelithiasis was obtained from UK Biobank (UKB). Two-sample MR analyses were performed to assess causalities between gut microbiota and cholelithiasis mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were used to determine the robustness of the MR results. Reverse MR analyses were performed to examine the reverse causal association. Our research results, based primarily on the IVW method, support the existence of a causal relationship between nine gut microbial taxa and cholelithiasis. We observed a positive association between Genus Butyrivibrio (p=0.032), Genus Lachnospiraceae_UCG_001 (p=0.015), Genus Ruminococcaceae_NK4A214_group (p=0.003), Genus Ruminococcaceae_UCG_011 (p=0.010) and cholelithiasis, while Order Rhodospirillales (p=0.031), Genus Actinomyces (p=0.010), Genus Phascolarctobacterium (p=0.036), Genus Rikenellaceae_RC9_gutgroup (p=0.023), Genus Ruminococcaceae_UCG_013 (p=0.022) may be associated with a reduced risk of cholelithiasis. We did not find a reverse causal relationship between cholelithiasis and 9 specific gut microbial taxa. This is the first mendelian randomization study to explore the causalities between specific gut microbiota taxa and cholelithiasis, which may provide new ideas and a theoretical basis for the prevention and treatment of cholelithiasis in the future.

Systematic analyses of GWAS summary statistics from UK Biobank identified novel susceptibility loci and genes for upper gastrointestinal diseases.

In recent decades, upper gastrointestinal (GI) diseases have been highly prevalent worldwide. Although genome-wide association studies (GWASs) have identified thousands of susceptibility loci, only a few of them were conducted for chronic upper GI disorders, and most of them were underpowered and with small sample sizes. Additionally, for the known loci, only a tiny fraction of heritability can be explained and the underlying mechanisms and related genes remain unclear. In this study, we conducted a multi-trait analysis by the MTAG software and a two-stage transcriptome-wide association study (TWAS) with UTMOST and FUSION for seven upper GI diseases (oesophagitis, gastro-oesophageal reflux disease, other diseases of oesophagus, gastric ulcer, duodenal ulcer, gastritis and duodenitis and other diseases of stomach and duodenum) based on summary GWAS statistics from UK Biobank. In the MTAG analysis, we identified 7 loci associated with these upper GI diseases, including 3 novel ones at 4p12 (rs10029980), 12q13.13 (rs4759317) and 18p11.32 (rs4797954). In the TWAS analysis, we revealed 5 susceptibility genes in known loci and identified 12 novel potential susceptibility genes, including HOXC9 at 12q13.13. Further functional annotations and colocalization analysis indicated that rs4759317 (A>G) driven the association for GWAS signals and expression quantitative trait loci (eQTL) simultaneously at 12q13.13. The identified variant acted by decreasing the expression of HOXC9 to affect the risk of gastro-oesophageal reflux disease. This study provided insights into the genetic nature of upper GI diseases.

Does Having Rheumatoid Arthritis Increase the Dose of Depression Medications? A Mendelian Randomization Study

Rheumatoid arthritis (RA) increases the risk of depression. However, studies on the effects of RA on the dose of depression medications are limited. Therefore, in this study, we used two-sample Mendelian randomization (MR) to explore whether RA increases the dose of depression medications and gain a more comprehensive understanding of the relationship between RA and depression. Two-sample MR was used to evaluate the causal effect of RA on the dose of depression medications. The aggregated data on RA originated from extensive genome-wide association studies (GWASs) of European descent (14,361 cases and 42,923 controls). The summary GWAS data for the dose of depression medications were derived from the FinnGen consortium (58,842 cases and 59,827 controls). Random effects inverse-variance weighted (IVW), MR-Egger regression, weighted median, and fixed effects IVW methods were used for the MR analysis. Random effects IVW was the primary method. The heterogeneity of the MR results was detected using the IVW Cochran's Q test. The pleiotropy of the MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, a leave-one-out analysis was performed to determine whether the MR results were affected by a specific single-nucleotide polymorphism (SNP). The primary method, random effects IVW, revealed that genetically predicted RA had a positive causal association with the dose of depression medications (Beta, 0.035; 95% confidence interval (CI), 0.007-0.064; p = 0.015). The IVW Cochran's Q test results revealed no heterogeneity in the MR analysis (p > 0.05). The MR-Egger regression and MR-PRESSO tests revealed that there was no pleiotropy in our MR analysis. The leave-one-out analysis confirmed that a single SNP did not affect the MR results, indicating the study's robustness. Using MR techniques, we discovered that having RA increases the dose of depression medications; however, the exact mechanisms and pathways still need to be further explored.

Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization.

Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)-for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferon-gamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factor-alpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream.

SDPRX: A statistical method for cross-population prediction of complex traits

Polygenic risk score (PRS) has demonstrated its great utility in biomedical research through identifying high-risk individuals for different diseases from their genotypes. However, the broader application of PRS to the general population is hindered by the limited transferability of PRS developed in Europeans to non-European populations. To improve PRS prediction accuracy in non-European populations, we develop a statistical method called SDPRX that can effectively integrate genome wide association study summary statistics from different populations. SDPRX automatically adjusts for linkage disequilibrium differences between populations and characterizes the joint distribution of the effect sizes of a variant in two populations to be both null, population specific, or shared with correlation. Through simulations and applications to real traits, we show that SDPRX improves the prediction performance over existing methods in non-European populations.