Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

Association of retinal age gap with chronic kidney disease and subsequent cardiovascular disease sequelae: a cross-sectional and longitudinal study from the UK Biobank.

Background: Chronic kidney disease (CKD) increases the risk of cardiovascular disease (CVD) and is more prevalent in older adults. Retinal age gap, a biomarker of aging based on fundus images, has been previously developed and validated. This study aimed to investigate the association of retinal age gap with CKD and subsequent CVD complications. Methods: A deep learning model was trained to predict the retinal age using 19 200 fundus images of 11 052 participants without any medical history at baseline. Retinal age gap, calculated as retinal age predicted minus chronological age, was calculated for the remaining 35 906 participants. Logistic regression models and Cox proportional hazards regression models were used for the association analysis. Results: A total of 35 906 participants (56.75 ± 8.04 years, 55.68% female) were included in this study. In the cross-sectional analysis, each 1-year increase in retinal age gap was associated with a 2% increase in the risk of CKD prevalence [odds ratio 1.02, 95% confidence interval (CI) 1.01-1.04, P = .012]. A longitudinal analysis of 35 039 participants demonstrated that 2.87% of them developed CKD in follow-up, and each 1-year increase in retinal age gap was associated with a 3% increase in the risk of CKD incidence (hazard ratio 1.03, 95% CI 1.01-1.05, P = .004). In addition, a total of 111 CKD patients (15.81%) developed CVD in follow-up, and each 1-year increase in retinal age gap was associated with a 10% increase in the risk of incident CVD (hazard ratio 1.10, 95% CI 1.03-1.17, P = .005). Conclusions: We found that retinal age gap was independently associated with the prevalence and incidence of CKD, and also associated with CVD complications in CKD patients. This supports the use of this novel biomarker in identifying individuals at high risk of CKD and CKD patients with increased risk of CVD.

Metabolic profiling reveals circulating biomarkers associated with incident and prevalent Parkinson's disease.

The metabolic profile predating the onset of Parkinson's disease (PD) remains unclear. We aim to investigate the metabolites associated with incident and prevalent PD and their predictive values in the UK Biobank participants with metabolomics and genetic data at the baseline. A panel of 249 metabolites was quantified using a nuclear magnetic resonance analytical platform. PD was ascertained by self-reported history, hospital admission records and death registers. Cox proportional hazard models and logistic regression models were used to investigate the associations between metabolites and incident and prevalent PD, respectively. Area under receiver operating characteristics curves (AUC) were used to estimate the predictive values of models for future PD. Among 109,790 participants without PD at the baseline, 639 (0.58%) individuals developed PD after one year from the baseline during a median follow-up period of 12.2 years. Sixty-eight metabolites were associated with incident PD at nominal significance (P < 0.05), spanning lipids, lipid constituent of lipoprotein subclasses and ratios of lipid constituents. After multiple testing corrections (P < 9 × 10-4), polyunsaturated fatty acids (PUFA) and omega-6 fatty acids remained significantly associated with incident PD, and PUFA was shared by incident and prevalent PD. Additionally, 14 metabolites were exclusively associated with prevalent PD, including amino acids, fatty acids, several lipoprotein subclasses and ratios of lipids. Adding these metabolites to the conventional risk factors yielded a comparable predictive performance to the risk-factor-based model (AUC = 0.766 vs AUC = 0.768, P = 0.145). Our findings suggested metabolic profiles provided additional knowledge to understand different pathways related to PD before and after its onset.

Sex-specific social, lifestyle, and physical health risk factors in cataracts development.

BACKGROUND: Cataract is a leading cause of blindness worldwide. However, little is known about sex differences in cataracts. Our study aimed to explore potential sex differences in the relationships between key social, lifestyle, and physical health risk factors and the incidence of cataracts. METHODS: A total of 117,972 participants from the UK Biobank were included in this prospective cohort study. Cox proportional hazard models were used to calculate hazard ratios (HRs) and female-to-male ratios of HRs (RHRs) with 95% confidence intervals (CIs) for cataract risk factors. Poisson regression was used to assess the incidence of cataracts (per 10,000 person-years). RESULTS: A total of 117,972 individuals without preexisting eye diseases were enroled in the analysis. 4172 subjects (54.8% female) were diagnosed with cataracts during follow-up. The crude incidence rates per 10,000 person-years were 35.06 for females and 29.15 for males. The incidence of cataracts increased in both males and females with factors such as Asian or Black ethnicity, smoking status, obesity, diabetes, and myopia. However, males who consumed alcohol or were unemployed suffered a greater risk of cataracts compared to their female counterparts, while high socioeconomic status, elevated blood pressure and metabolic syndrome were associated with a greater risk of cataracts in females than in males. CONCLUSION: This study provides a comprehensive overview of sex differences in the associations between cataracts and various risk factors. Our findings highlight that socioeconomic and lifestyle risk factors are more strongly linked to cataract risk in males, whereas females with systemic diseases face a greater risk of developing cataract.

Accelerometer-Measured Daily Behaviors That Mediate the Association Between Refractive Status and Depressive Disorders.

Purpose: To identify the accelerometer-measured daily behaviors that mediate the association of refractive status with depressive disorders and enhance the understanding of behavioral differences in depression. Methods: Participants with baseline mean spherical equivalent (MSE) and 7-day accelerometer measurements from the UK Biobank were included in this cohort study. Refractive status was categorized as hyperopia and non-hyperopia. Four daily behaviors, including moderate to vigorous intensity physical activity (MVPA), light physical activity (LPA), sedentary, and sleep were recorded between 2013 and 2015. We also assessed 24-hour behavior patterns. Depression cases were defined through both questionnaires and hospital records over 10 years of follow-up. Results: Among 20,607 individuals, every 0.5-diopter increase in MSE was associated with a 6% higher risk of depressive disorders, with hyperopia participants at a higher risk than non-hyperopia participants (odds ratio, 1.14; 95% confidence interval, 1.05-1.23; P = 0.001). MVPA and sleep time significantly correlated with depressive disorders, with odds ratios of 0.79 and 1.14 (P < 0.05). MSE showed significant correlations with all four behaviors. The effects of MVPA and sleep duration on MSE and depressive disorders varied throughout the day. Mediation analyses showed that MVPA and sleep partially mediated the relationship between MSE and depressive disorders, with 35.2% of the association between moderate to high hyperopia and depression mediated by MVPA. Conclusions: Physical activity and sleep significantly mediate the relationship between MSE and depressive disorders. Translational Relevance: The mediation effect of MVPA highlights its therapeutic potential in reducing the risk of depression among individuals with moderate to severe hyperopia. Interventions aimed at increasing daytime MVPA and decreasing daytime sleep could enhance mental health in this vulnerable group.

Association of greenspace and natural environment with brain volumes mediated by lifestyle and biomarkers among urban residents.

OBJECTIVES: To examine the associaiton between environmental measures and brain volumes and its potential mediators. STUDY DESIGN: This was a prospective study. METHODS: Our analysis included 34,454 participants (53.4% females) aged 40-73 years at baseline (between 2006 and 2010) from the UK Biobank. Brain volumes were measured using magnetic resonance imaging between 2014 and 2019. RESULTS: Greater proximity to greenspace buffered at 1000 m at baseline was associated with larger volumes of total brain measured 8.8 years after baseline assessment (standardized ß (95% CI) for each 10% increment in coverage: 0.013(0.005,0.020)), grey matter (0.013(0.006,0.020)), and white matter (0.011(0.004,0.017)) after adjustment for covariates and air pollution. The corresponding numbers for natural environment buffered at 1000 m were 0.010 (0.004,0.017), 0.009 (0.004,0.015), and 0.010 (0.004,0.016), respectively. Similar results were observed for greenspace and natural environment buffered at 300 m. The strongest mediator for the association between greenspace buffered at 1000 m and total brain volume was smoking (percentage (95% CI) of total variance explained: 7.9% (5.5-11.4%)) followed by mean sphered cell volume (3.3% (1.8-5.8%)), vitamin D (2.9% (1.6-5.1%)), and creatinine in blood (2.7% (1.6-4.7%)). Significant mediators combined explained 18.5% (13.2-25.3%) of the association with total brain volume and 32.9% (95% CI: 22.3-45.7%) of the association with grey matter volume. The percentage (95% CI) of the association between natural environment and total brain volume explained by significant mediators combined was 20.6% (14.7-28.1%)). CONCLUSIONS: Higher coverage percentage of greenspace and environment may benefit brain health by promoting healthy lifestyle and improving biomarkers including vitamin D and red blood cell indices.

Shared genetic aetiology of Alzheimer's disease and age-related macular degeneration by APOC1 and APOE genes.

Background: Alzheimer's disease (AD) and age-related macular degeneration (AMD) share similar pathological features, suggesting common genetic aetiologies between the two. Investigating gene associations between AD and AMD may provide useful insights into the underlying pathogenesis and inform integrated prevention and treatment for both diseases. Methods: A stratified quantile-quantile (QQ) plot was constructed to detect the pleiotropy among AD and AMD based on genome-wide association studies data from 17 008 patients with AD and 30 178 patients with AMD. A Bayesian conditional false discovery rate-based (cFDR) method was used to identify pleiotropic genes. UK Biobank was used to verify the pleiotropy analysis. Biological network and enrichment analysis were conducted to explain the biological reason for pleiotropy phenomena. A diagnostic test based on gene expression data was used to predict biomarkers for AD and AMD based on pleiotropic genes and their regulators. Results: Significant pleiotropy was found between AD and AMD (significant leftward shift on QQ plots). APOC1 and APOE were identified as pleiotropic genes for AD-AMD (cFDR <0.01). Network analysis revealed that APOC1 and APOE occupied borderline positions on the gene co-expression networks. Both APOC1 and APOE genes were enriched on the herpes simplex virus 1 infection pathway. Further, machine learning-based diagnostic tests identified that APOC1, APOE (areas under the curve (AUCs) >0.65) and their upstream regulators, especially ZNF131, ADNP2 and HINFP, could be potential biomarkers for both AD and AMD (AUCs >0.8). Conclusion: In this study, we confirmed the genetic pleiotropy between AD and AMD and identified APOC1 and APOE as pleiotropic genes. Further, the integration of multiomics data identified ZNF131, ADNP2 and HINFP as novel diagnostic biomarkers for AD and AMD.

Epidemiologic association and shared genetic architecture between cataract and hearing difficulties among middle-aged and older adults.

Age-related cataract and hearing difficulties are major sensory disorders that often co-exist in the global-wide elderly and have a tangible influence on the quality of life. However, the epidemiologic association between cataract and hearing difficulties remains unexplored, while little is known about whether the two share their genetic etiology. We first investigated the clinical association between cataract and hearing difficulties using the UK Biobank covering 502,543 individuals. Both unmatched analysis (adjusted for confounders) and a matched analysis (one control matched for each patient with cataract according to confounding factors) were undertaken and confirmed that cataract was associated with hearing difficulties (OR, 2.12; 95% CI, 1.98-2.27; OR, 2.03; 95% CI, 1.86-2.23, respectively). Furthermore, we explored and quantified the shared genetic architecture of these two complex sensory disorders at the common variant level using the bivariate causal mixture model (MiXeR) and conditional/conjunctional false discovery rate method based on the largest available genome-wide association studies of cataract (N = 585,243) and hearing difficulties (N = 323,978). Despite detecting only a negligible genetic correlation, we observe polygenic overlap between cataract and hearing difficulties and identify 6 shared loci with mixed directions of effects. Follow-up analysis of the shared loci implicates candidate genes QKI, STK17A, TYR, NSF, and TCF4 likely contribute to the pathophysiology of cataracts and hearing difficulties. In conclusion, this study demonstrates the presence of epidemiologic association between cataract and hearing difficulties and provides new insights into the shared genetic architecture of these two disorders at the common variant level.

The association between cataract surgery and mental health in older adults: a review.

BACKGROUND: Although cataract surgery has been proposed as a potentially modifiable protective factor for enhancing emotional well-being in cataract patients, studies examining the relationship between anxiety or depression and cataract surgery have yielded inconsistent findings. This review summarizes existing evidence to establish whether cataract surgery is associated with depression and anxiety in older adults. METHODS: A literature search was conducted across PubMed, Medline, Web of Science, and Embase databases. An initial screening by abstracts and titles was performed, followed by a review and assessment of the methodological quality of the relevant full papers, and final inclusion of 44 studies were deemed eligible for inclusion in this review. RESULTS: Among 44 included studies, 36 studies (81.8%) were observational studies concerning the association of cataract surgery or cataracts with anxiety or depression, four studies (9.1%) were interventional studies, and four studies (9.1%) were reviews. Cataract surgery notably enhances the mental health of individuals with impaired vision. However, the multifaceted nature of psychological well-being, influenced by various factors, suggests that cataract surgery may not address all aspects comprehensively. Additionally, preoperative anxiety and depression significantly impact cataract surgery outcomes. CONCLUSION: Vision impairment in older adults is closely associated with increased symptoms of depression and anxiety. While surgical intervention for cataracts improves these symptoms, it might be less effective for mental disorders with multifactorial causes. Notably, anxiety or depression poses challenges to successful preoperative and intraoperative cataract surgeries.

Evaluation of the Observational Associations and Shared Genetics Between Glaucoma With Depression and Anxiety.

Purpose: Glaucoma, a leading cause of blindness worldwide, is suspected to exhibit a notable association with psychological disturbances. This study aimed to investigate epidemiological associations and explore shared genetic architecture between glaucoma and mental traits, including depression and anxiety. Methods: Multivariable logistic regression and Cox proportional hazards regression models were employed to investigate longitudinal associations based on UK Biobank. A stepwise approach was used to explore the shared genetic architecture. First, linkage disequilibrium score regression inferred global genetic correlations. Second, MiXeR analysis quantified the number of shared causal variants. Third, specific shared loci were detected through conditional/conjunctional false discovery rate (condFDR/conjFDR) analysis and characterized for biological insights. Finally, two-sample Mendelian randomization (MR) was conducted to investigate bidirectional causal associations. Results: Glaucoma was significantly associated with elevated risks of hospitalized depression (hazard ratio [HR] = 1.54; 95% confidence interval [CI], 1.01-2.34) and anxiety (HR = 2.61; 95% CI, 1.70-4.01) compared to healthy controls. Despite the absence of global genetic correlations, MiXeR analysis revealed 300 variants shared between glaucoma and depression, and 500 variants shared between glaucoma and anxiety. Subsequent condFDR/conjFDR analysis discovered 906 single-nucleotide polymorphisms (SNPs) jointly associated with glaucoma and depression and two associated with glaucoma and anxiety. The MR analysis did not support robust causal associations but indicated the existence of pleiotropic genetic variants influencing both glaucoma and depression. Conclusions: Our study enhances the existing epidemiological evidence and underscores the polygenic overlap between glaucoma and mental traits. This observation suggests a correlation shaped by pleiotropic genetic variants rather than being indicative of direct causal relationships.

Combination of serum markers with optical coherence tomography angiography for evaluating neuromyelitis optica spectrum disorders and multiple sclerosis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS), autoimmune inflammatory diseases of the central nervous system, affect the optic nerve and brain. A lumbar puncture to obtain biomarkers is highly invasive. Serum biomarkers and optical coherence tomography angiography (OCTA) are more accessible and less expensive than magnetic resonance imaging and provide reliable, reproducible measures of neuroaxonal damage. This study investigated the association between serum neurofilament light chain (sNfL), serum glial fibrillary acidic protein (sGFAP), and OCTA metrics. Serum sNfL and sGFAP levels, OCTA values, and clinical characteristics were compared among 91 patients with NMOSD, 81 patients with MS, and 34 healthy controls (HCs) at baseline and 1-year follow-up. RESULTS: sNfL and sGFAP levels were higher while the sGFAP/sNfL quotients were significantly lower in NMOSD and MS patients than those in HCs. At baseline, the average thicknesses of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGC-IPL) were significantly smaller in NMOSD and MS patients than those in HCs (pRNFL: MS 92.0 [80.2; 101] µm, NMOSD 80.0 [59.0; 95.8] µm, vs HC 99.0 [92.0; 104] µm, p < 0.001; mGC-IPL: MS 74.5 [64.2; 81.0] µm, NMOSD 68.0 [56.0; 81.0] µm, vs HC 83.5 [78.0; 88.0] µm, p < 0.001). The vessel density (VD) and perfusion density (PD) were increased in MS patients without optic neuritis compared to HCs (VD: MS 16.7 [15.6; 17.9] HC 15.3 [13.4; 16.9], p = 0.008; PD: MS 0.41 [0.38; 0.43], HC 0.37 [0.32; 0.41], p = 0.017). In NMOSD patients without optic neuritis, sNfL was significantly associated with PD at baseline (r = 0.329, q = 0.041). The baseline and follow-up values of the sNfL level and average pRNFL and mGC-IPL thicknesses in MS patients showed significant differences. NMOSD patients showed significant differences between baseline and follow-up sNfL and sGFAP levels but not OCTA metrics. CONCLUSION: Changes in retinal microvasculature might occur earlier than those in retinal structure and may therefore serve as a promising diagnostic marker for early NMOSD. The combination of serum markers and OCTA metrics could be used to evaluate and differentiate between MS and NMOSD.

Metabolomic age and risk of 50 chronic diseases in community-dwelling adults: A prospective cohort study.

It is unclear how metabolomic age is associated with the risk of a wide range of chronic diseases. Our analysis included 110,692 participants (training: n = 27,673; testing: n = 27,673; validating: n = 55,346) aged 39-71 years at baseline (2006-2010) from the UK Biobank. Incident chronic diseases were identified using inpatient records, or death registers until January 2021. Predicted metabolomic age was trained and tested based on 168 metabolomics. Metabolomic age was linked to the risk of 50 diseases in the validation dataset. The median follow-up duration for individual diseases ranged from 11.2 years to 11.9 years. After controlling for false discovery rate, chronological age-adjusted age gap (CAAG) was significantly associated with the incidence of 25 out of 50 chronic diseases. After adjustment for full covariates, associations with 15 chronic diseases remained significant. Greater CAAG was associated with increased risk of eight cardiometabolic disorders (including cardiovascular diseases and diabetes), some cancers, alcohol use disorder, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease and age-related macular degeneration. The association between CAAG and risk of peripheral vascular disease, other cardiac diseases, fracture, cataract and thyroid disorder was stronger among individuals with unhealthy diet than in those with healthy diet. The association between CAAG and risk of some conditions was stronger in younger individuals, those with metabolic disorders or low education. Metabolomic age plays an important role in the development of multiple chronic diseases. Healthy diet and high education may mitigate the risk for some chronic diseases due to metabolomic age acceleration.

Leading determinants of incident dementia among individuals with and without the apolipoprotein E ε4 genotype: a retrospective cohort study.

BACKGROUND: Little is known regarding the leading risk factors for dementia/Alzheimer's disease (AD) in individuals with and without APOE4. The identification of key risk factors for dementia/Alzheimer's disease (AD) in individuals with and without the APOE4 gene is of significant importance in global health. METHODS: Our analysis included 110,354 APOE4 carriers and 220,708 age- and sex-matched controls aged 40-73 years at baseline (between 2006-2010) from UK Biobank. Incident dementia was ascertained using hospital inpatient, or death records until January 2021. Individuals of non-European ancestry were excluded. Furthermore, individuals without medical record linkage were excluded from the analysis. Moderation analysis was tested for 134 individual factors. RESULTS: During a median follow-up of 11.9 years, 4,764 cases of incident all-cause dementia and 2065 incident AD cases were documented. Hazard ratios (95% CIs) for all-cause dementia and AD associated with APOE4 were 2.70(2.55-2.85) and 3.72(3.40-4.07), respectively. In APOE4 carriers, the leading risk factors for all-cause dementia included low self-rated overall health, low household income, high multimorbidity risk score, long-term illness, high neutrophil percentage, and high nitrogen dioxide air pollution. In non-APOE4 carriers, the leading risk factors included high multimorbidity risk score, low overall self-rated health, low household income, long-term illness, high microalbumin in urine, high neutrophil count, and low greenspace percentage. Population attributable risk for these individual risk factors combined was 65.1%, and 85.8% in APOE4 and non-APOE4 carriers, respectively. For 20 risk factors including multimorbidity risk score, unhealthy lifestyle habits, and particulate matter air pollutants, their associations with incident dementia were stronger in non-APOE4 carriers. For only 2 risk factors (mother's history of dementia, low C-reactive protein), their associations with incident all-cause dementia were stronger in APOE4 carriers. CONCLUSIONS: Our findings provide evidence for personalized preventative approaches to dementia/AD in APOE4 and non-APOE4 carriers. A mother's history of dementia and low levels of C-reactive protein were more important risk factors of dementia in APOE4 carriers whereas leading risk factors including unhealthy lifestyle habits, multimorbidity risk score, inflammation and immune-related markers were more predictive of dementia in non-APOE4 carriers.