Association between migraine and primary open-angle glaucoma: A two-sample Mendelian randomization study

The correlation between obesity and primary open-angle glaucoma (POAG) has not yet been fully established. The aim of this study was to investigate the causal relationship between obesity and POAG by a two-sample Mendelian randomization (MR) study. In this study, body mass index (BMI), an index to evaluate general obesity, and waist and hip circumference, indices to evaluate abdominal obesity, were selected as exposures in MR analysis. Single-nucleotide polymorphisms (SNPs) were chosen as instrumental variables (IVs). Summary data from genome-wide association studies (GWASs) based on a European ancestry by Locke et al., with regard to BMI, and Shungin et al., with regard to waist and hip circumference, were used. Genetic predictors of POAG were obtained from public GWAS summary data. To assess the causal effect of obesity on POAG, the inverse variance-weighted (IVW) method was used as the primary method, and other methods, such as MR–Egger, weighted median, simple mode, and weighted mode, were also used as complementary analyses. Finally, we performed Cochran’s Q statistic to assess heterogeneity, and sensitivity analysis was performed to evaluate the reliability and stability of the MR results. MR analysis showed that BMI has a positive effect on the risk of POAG, with 1 standard deviation (SD) increase in BMI; the risk of POAG increases by approximately 90.9% [OR = 1.909; 95% CI= (1.225, 2.975); p = 0.0042)] (analyzed by IVW); there were no heterogeneity and pleiotropy in the result; and waist circumference also had a positive effect on the risk of POAG [OR = 2.319; 95% CI= (1.071, 5.018); p = 0.033)] analyzed by weighted median. As hip circumference increases, with 1 SD increase in hip circumference, the risk of POAG increases by approximately 119% [OR = 2.199; 95% CI= (1.306, 3.703); p = 0.00305)] estimated by IVW, there were not heterogeneity and pleiotropy as for the result. Our study for the first time confirms that obesity might increase the risk of POAG using two-sample MR analysis. These results might provide guidance on the prevention and treatment of POAG.

PurposeTo investigate the association of genetically determined primary open-angle glaucoma (POAG), myopic refractive error (RE), type 2 diabetes (T2D), blood pressure (BP), body mass index (BMI), cigarette smoking, and alcohol consumption with the risk of age-related cataract.MethodsTo assess potential causal effects of clinical or behavioral factors on cataract risk, we conducted two-sample Mendelian randomization analyses. Genetic instruments, based on common genetic variants associated with risk factors at genome-wide significance (P < 5 × 10−8), were derived from published genome-wide association studies (GWAS). For age-related cataract, we used GWAS summary statistics from our previous GWAS conducted in the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (28,092 cataract cases and 50,487 controls; all non-Hispanic whites) or in the UK Biobank (31,852 cataract cases and 428,084 controls; all European-descent individuals). We used the inverse-variance weighted (IVW) method as our primary source of Mendelian randomization estimates and conducted common sensitivity analyses.ResultsWe found that genetically determined POAG and mean spherical equivalent RE were significantly associated with cataract risk (IVW model: odds ratio [OR] = 1.04; 95% confidence interval [CI], 1.01–1.08; P = 0.018; per diopter more hyperopic: OR = 0.92; 95% CI, 0.89–0.93; P = 6.51 × 10−13, respectively). In contrast, genetically determined T2D, BP, BMI, cigarette smoking, or alcohol consumption were not associated with cataract risk (P > 0.05).ConclusionsOur results provide evidence that genetic risks for POAG and myopia may be causal risk factors for age-related cataract. These results are consistent with previous observational studies reporting associations of myopia with cataract risk. This information may support population cataract risk stratification and screening strategies.

BackgroundThe causal effects of plasma lipid concentrations and the risk of primary open angle glaucoma (POAG) are still unclear. Thus, the purpose of this study was to identify, applying a two-sample Mendelian randomization (MR) analysis, whether plasma lipid concentrations are causally associated with the risk of POAG.MethodsTwo-sample MR analysis of data from a genome-wide association study (GWAS) was performed to investigate the causal role of plasma lipid levels and POAG. A total of 185 independent single-nucleotide polymorphisms (SNPs) associated with plasma lipid levels were selected as instrumental variables (IVs). The SNPs were obtained from a meta-analysis of GWAS based on 188,577 European-ancestry individuals for MR analyses. Association with POAG for the SNPs was obtained from a GWAS conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals. Four MR methods (inverse variance weighted [IVW], weighted mode, weighted median, and MR-Egger regression) were applied to obtain the overall causal estimate for multiple, instrumental SNPs.ResultsUsing the IVW analysis method, no evidence was found to support a causal association between plasma LDL-C level and POAG risk (β = − 0.00026; 95% CI = -0.00062, 0.00011; P = 0.165) with no significant heterogeneity among SNPs. The overall causal estimate between plasma LDL-C level and POAG was consistent using the other three MR methods. Using the four MR methods, no evidence of an association between plasma HDL-C (β = 0.00023; 95% CI = -0.00015, 0.00061; P = 0.238; IVW method) or TG levels (β = − 0.00028; 95% CI = -0.00071, 0.00015; P = 0.206; IVW method) and POAG risk was found. Sensitivity analyses did not reveal any sign of directional pleiotropy.ConclusionsThe present study did not find any evidence for a causal association between plasma lipid levels and POAG risk. Further research is needed to elucidate the potential biological mechanisms to provide a reasonable interpretation for these results.

Background/ObjectivesGlaucoma is the leading cause of irreversible blindness, disproportionately affecting individuals of African ancestry. Limited research has examined the impact of neighbourhood quality and socioeconomic factors on primary open-angle glaucoma (POAG) risk in this population. This study aims to address these gaps by evaluating associations between ocular health and neighbourhood characteristics using geospatial data.Subjects/MethodsWe conducted a case-control study with 5192 African ancestry individuals from the Philadelphia area using data from the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. Geocoded U.S. Census data were merged with individual-level demographics and neighbourhood-level measures, including air quality, food accessibility, and socioeconomic indicators, to assess their association with glaucoma risk and severity.ResultsThe study included 3039 controls (58.5%) and 2153 POAG cases (41.5%). Higher POAG risk was associated with older age (OR 1.72 per 10-year increase, p < 0.001), male gender (OR 2.04, p < 0.001), lower BMI (OR 0.87 per 10 kg/m2 increase, p = 0.003), and nonuse of alcohol (OR 0.56 for alcohol use, p < 0.001). Low food access was more common in controls (OR 0.86, p = 0.03), and severe POAG cases were associated with lower homeownership rates (OR 0.95 per 10% increase, p = 0.049). However, most socioeconomic and environmental factors (air quality, education, income, occupation, family structure) were not significantly linked to POAG risk or severity.ConclusionSocioeconomic status did not significantly protect against POAG in African ancestry individuals. Individual factors were more influential, suggesting neighbourhood and socioeconomic factors may have a lesser impact than previously hypothesised.

Natural hair color and skin cancers: A two-sample Mendelian randomization study

To evaluate outcomes of Trabectome on pigmentary glaucoma (PG) patients compared to matched controls with primary open angle glaucoma (POAG). Prospective comparison study PARTICIPANTS: A total of 101 POAG cases were matched with 101 PG cases. Data of the patients diagnosed with PG or POAG was obtained from Trabectome Study Group Database. A one-to-one exact matching was performed between POAG and pigmentary cases based on type of surgery, baseline IOP and baseline number of glaucoma medications. IOP and number of glaucoma medications were compared between groups by Wilcoxon test. Success was defined as IOP ≤ 21 mmHg, at least 20% IOP reduction from baseline for two consecutive visits after 3 months and no secondary surgery. Success rate after Trabectome surgery in PG patients. Baseline IOP for PG is 24.4 ± 7.7 mmHg and 24.2 ± 7.5 mmHg for POAG (P = 1.0), while baseline number of glaucoma medications was 2.8 ± 1.2 mmHg for PG and 2.8 ± 1.2 mmHg for POAG (P = 1.0). Postoperative IOP values at 12 months were 17.1 ± 5.0 for PG cases and 15.9 ± 4.2 mmHg for POAG cases. Postoperative number of glaucoma medications at 12 month was 2.1 ± 1.4 in PG cases and 2.4 ± 1.3 in POAG cases. There was no statistically significant difference between groups in IOP or number of medications at any time point. Survival rate at 12 months was 92% and 86% in PG and POAG, respectively (P = 0.47). Six PG cases and nine POAG cases required secondary surgery. Trabectome provides similar outcomes to PG patients and POAG patients.

Background: Previous Mendelian randomization (MR) studies showed an association between hypothyroidism and cataract and between high-normal free thyroxine (FT4) and late age-related macular degeneration (AMD), but not between FT4, thyroid stimulating hormone (TSH), or hyperthyroidism and diabetic retinopathy or cataract. These studies included a limited number of genetic variants for thyroid function and did not investigate autoimmune thyroid disease (AITD) or glaucoma, include bidirectional and multivariable MR (MVMR), and examine sex differences or potential mediation effects of diabetes. We aimed to address this knowledge gap. Methods: We examined the causality and directionality of the associations of AITD, and FT4 and TSH within the reference range with common age-related eye diseases (diabetic retinopathy, cataract, early and late AMD, and primary open-angle glaucoma). We conducted a bidirectional two-sample MR study utilizing publicly available genome-wide association study (GWAS) summary statistics from international consortia (ThyroidOmics, International AMD Genetics Consortium, deCODE, UK Biobank, FinnGen, and DIAGRAM). Bidirectional MR tested directionality, whereas MVMR estimated independent causal effects. Furthermore, we investigated type 1 diabetes (T1D) and type 2 diabetes (T2D) as potential mediators. Results: Genetic predisposition to AITD was associated with increased risk of diabetic retinopathy (p = 3 × 10-4), cataract (p = 3 × 10-3), and T1D (p = 1 × 10-3), but less likely T2D (p = 0.01). MVMR showed attenuated estimates for diabetic retinopathy and cataract when adjusting for T1D, but not T2D. We found pairwise bidirectional associations between AITD, T1D, and diabetic retinopathy. Genetic predisposition to both T1D and T2D increased the risk of diabetic retinopathy and cataract (p < 4 × 10-4). Moreover, genetically predicted higher FT4 within the reference range was associated with an increased risk of late AMD (p = 0.01), particularly in women (p = 7 × 10-3). However, we neither found any association between FT4 and early AMD nor between TSH and early and late AMD. No other associations were observed. Conclusions: Genetic predisposition to AITD is associated with risk of diabetic retinopathy and cataract, mostly mediated through increased T1D risk. Reciprocal associations between AITD, diabetic retinopathy, and T1D imply a shared autoimmune origin. The role of FT4 in AMD and potential sex discrepancies needs further investigation.

Association Between Glycemic Traits and Primary Open-Angle Glaucoma: A Mendelian Randomization Study in the Japanese Population

Joint effects of air pollution and genetic susceptibility on incident primary open-angle glaucoma

Observational studies suggest a potential link between obesity and constipation, but existing results are conflicting. Therefore, we conducted a Mendelian randomization (MR) study and meta-analysis to assess the causal relationship between obesity and the risk of constipation. In this study, independent genetic variants closely related to constipation were acquired from a genome-wide association study (GWAS) to analyze the relationship between genetically predisposed obesity and the risk of constipation. Waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and body mass index (BMI) were collected from the GWAS. Then, the causal relationship between constipation and obesity was explored using a two-sample MR study in both directions. The robustness of the results was evaluated using sensitivity analysis. Furthermore, a systemic review and meta-analysis were performed to calculate relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Subgroup analyses stratified by age and obesity degree were completed. To evaluate whether the current studies were affected by unmeasured confounders, E-values of each study were determined. In MR analysis, the incidence of constipation increased with the increase in BMI [inverse variance-weighted (IVW) odds ratio (OR) = 1.138 (1.029, 1.260), p = 0.012]. In addition, constipation was impacted by WC [IVW OR = 1.220 (1.061, 1.402), p = 0.005]. However, there was no evidence that WHR [IVW OR = 1.833 (0.826, 4.065), p = 0.136] or HC [IVW OR = 0.949, (0.836, 1.077), p = 0.415] has a causal effect on constipation. In reverse MR analysis, there was no evidence supporting the causality between constipation and obesity [BMI IVW OR = 1.010 (0.998, 1.022), p = 0.089; WHR IVW OR = 1.000 (0.946, 1.057), p = 0.994; WC IVW OR = 1.008 (0.995, 1.022), p = 0.217; HC IVW OR = 0.996 (0.982, 1.011), p = 0.626]. In the meta-analysis, 14 eligible articles were included, involving 43,488 subjects. According to the results of the meta-analysis, the risk of obesity and overweight significantly increased the risk of constipation [RR = 1.145 (0.952, 1.376)]. This was consistent with the MR analysis results. Moreover, overweight and obesity were significantly related to a higher constipation risk among children [overweight RR = 1.112 (0.943, 1.312); obesity RR = 1.407 (1.282, 1.544)]. Additionally, overweight in adults could decrease the risk of constipation [RR = 0.940 (0.827, 1.068)]. Nevertheless, no significant association was observed between obesity in adults and the risk of constipation [RR = 1.000 (0.768, 1.303)]. Sensitivity analysis revealed the robustness of our findings. In this combined MR study and meta-analysis, obesity is associated with an increased risk of constipation. The MR analysis demonstrates the causal relationship between genetically predisposed obesity and the risk of constipation. More research is required to investigate the potential correlation between obesity and the risk of constipation and associated mechanisms.

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data.We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio.We tested 13 377 protein–disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein–disease pairs, leading to 50 unique protein–disease associations. Notably, 23 of 50 protein–disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume.Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer’s disease; the interleukin-6 pathway (CTF1) in Parkinson’s disease; lysosomes (TPP1), blood–brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood–brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.

The development of ankylosing spondylitis (AS) is closely related to autoimmune system dysfunction. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that is a risk factor for many diseases. This study aimed to investigate the causal relationship between T1DM mellitus and AS genetically. A genome-wide association study (GWAS) of causal relationships between exposure (T1DM) and outcome (AS) was performed using summary data from the GWAS database. We conducted a two-sample Mendelian randomization (MR) study of these two diseases. Inverse variance weighting (IVW) was used as the primary analysis method, with MR Egger, weighted median, and weighted mode used as supplementary methods. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-Pleiotropy RESidual Sum and outlier methods, leave-one-out analysis, and funnel plots. A total of 11 single nucleotide polymorphisms (SNPs)were identified for instrumental variables(IVs) for MR analysis.IVW found that T1DM was causally associated with AS ((IVW: OR = 1.0006 (95% CI 1.0001, 1.0011), p = 0.0057; MR-Egger: OR = 1.0003 (95% CI 0.9995, 1.0012), p = 0.4147; weighted median: OR = 1.0006 (95% CI 1.0003, 1.0008), p = 0.0001; weighted mode: OR = 1.0007 (95% CI 1.0005, 1.0009), p = 0.0001). No horizontal pleiotropy was found for the MR-Egger intercept, and leave -one-out analysis found that the results remained stable after the removal of individual SNPs. The results of the two-sample MR analysis supported a causal relationship between T1DM and AS risk.

Background Observational evidence indicates that patients with atrial fibrillation (AF) are at a four- to fivefold increased risk of stroke. By two-sample mendelian randomization (MR), we have shown in our previous work that specifically the cardioembolic stroke subtype is caused by AF. This risk elevation is however variable and appears to be modulated by other risk factors such as hypertension traits and coronary artery disease (CAD). Purpose This study seeks to determine (1) whether genetic predisposition to cardioembolic stroke by AF is independent from modulators, and (2) whether the other stroke subtypes are causally linked with different exposures. Methods The associations between AF, hypertension traits, and CAD as exposures and stroke subtypes as outcomes were individually tested in a two-sample mendelian randomisation (MR) analysis using genetic instruments from publicly available genome-wide association studies (GWAS) in large cohorts. For atrial fibrillation, genetic instruments were obtained from the dataset by Nielsen et al. with 60,620 atrial fibrillation cases and 970,216 controls, collected from six contributing studies including the AFGen Consortium. Associations with stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67, 162 cases; 454, 450 controls). The genetic markers for hypertension traits were taken from a GWAS by Evangelou et al. which combines data from the UK Biobank (UKB) and the International Consortium of Blood Pressure (ICBP) with a total sample size of 757,601 individuals. Genetic instruments for CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls from 48 studies). Several MR regression methods such as MR-Egger regression and inverse-variance weighted regression as well as sensitivity analyses were applied. A multivariable MR model served to determine which of the exposures had an independent causal effect on each of the stroke subtypes. Results Atrial fibrillation turned out to be the sole independent causal risk factor for cardioembolic stroke with a beta coefficient of 0.75 (SE = ± 0.04; P = 8.59 x 10e-100) and an OR of 2.16 (1.97-2.27) in a multivariable model adjusted for AF, CAD, systolic blood pressure (SBP) and diastolic blood pressure. In this model, SBP and CAD were non-causative for cardioembolic stroke, but exhibited significant, albeit weak causal associations with small vessel stroke (SBP: OR 1.04 (1.02-1.06); CAD: OR 1.14 (1.02-1.28)) and large artery stroke (SBP: OR 1.09 (1.06-1.11); CAD: OR 1.59 (1.40-1.79). Conclusions Causality of the association between the cardioembolic stroke subtype and AF is independent from modulators such as SBP and CAD. However, SBP and CAD play a complementary role as causal exposures for small vessel and large artery stroke which in turn are not causally linked with AF.

In order to elucidate the correlation and its pathways between liver diseases and vascular dementia (VaD). We performed two-sample Mendelian randomization (MR) study. We performed a two-sample MR study using summary-level genome-wide association study (GWAS) data for 4 liver diseases (nonalcoholic fatty liver disease [NAFLD], nonalcoholic steatohepatitis [NASH], alcoholic liver disease [ALD], and fibrosis/cirrhosis [FACOL]) and VaD. Inverse variance weighted (IVW) served as the primary analysis, complemented by a suite of sensitivity analyses (Cochran Q test, MR-Egger regression and MR pleiotropy residual sum and outlier [MR-PRESSO]). Furthermore, multivariable MR (MVMR) was conducted to adjust for key metabolic traits, including fasting glucose and triglycerides. The IVW analysis indicated that no significant causal associations were found between any of the 4 liver diseases and the risk of VaD. Sensitivity analyses indicated that the results for NAFLD and FACOL may be affected by heterogeneity, and NAFLD may also be affected by horizontal pleiotropy. Crucially, after adjusting for genetic liability to elevated triglycerides or fasting glucose in MVMR analyses, the initially null association for NAFLD became significant, revealing a protective effect against VaD. Associations for other liver diseases remained null after adjustment. This MR study found no direct causal link between liver diseases and VaD. However, adjusting for glucose or triglycerides revealed a potential protective effect of NAFLD, suggesting metabolic factors may confound the association. Further research is warranted to disentangle the complex relationship between these health conditions.

BackgroundObservational studies have suggested that hearing impairment (HI) was associated with the risk of falls, but it remains unclear if this association is of causal nature.MethodsA two-sample Mendelian randomization (MR) study was conducted to investigate the causal association between HI and falls in individuals of European descent. Summary data on the association of single nucleotide polymorphisms (SNPs) with HI were obtained from the hitherto largest genome-wide association study (GWAS) (n = 323,978), and statistics on the association of SNPs with falls were extracted from another recently published GWAS (n = 461,725). MR Steiger filtering method was applied to determine the causal direction between HI and falls. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal association between HI and falls, whereas weighted median, simple mode, weighted mode, and MR-Egger methods were used as complementary analyses. The MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were performed to detect the potential directional pleiotropy and heterogeneity, respectively. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association.ResultsA total of 18 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The positive causality between HI and risk of falls was indicated by IVW [OR 1.108 (95% CI 1.028, 1.194), p = 0.007]. The sensitivity analyses yielded comparable results. The “leave-one-out” analysis proved that lack of a single SNP did not affect the robustness of our results. The MR-Egger intercept test exhibited that genetic pleiotropy did not bias the results [intercept = −2.4E−04, SE = 0.001, p = 0.832]. Cochran's Q test revealed no heterogeneity.ConclusionOur MR study revealed a causal association between genetically predicted HI and falls. These results provide further evidence supporting the need to effectively manage HI to minimize fall risks and improve quality of life.