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To evaluate the association between a polygenic risk score (PRS) for primary open-angle glaucoma (POAG) and the age at the first trabeculectomy and the need for bilateral trabeculectomy.Retrospective observational cohort study.Nine hundred and three genotyped participants with POAG from the Australian and New Zealand Registry of Advanced Glaucoma.The ocular surgical history of these participants was reviewed and the following parameters were recorded: age at diagnosis, age at trabeculectomy, and lateraly of trabeculectomy. Multivariate linear regression analyses correlated glaucoma PRSs with age at trabeculectomy, and laterality of trabeculectomy. For descriptive purposes, the participants were stratified into the top decile, intermediate group (10th-89th percentile), and bottom decile.Age at trabeculectomy, and laterality of trabeculectomy.Higher PRS was associated with younger age at the first trabeculectomy (β, -1.94 years/standard deviation; 95% confidence interval [CI], - 0.41 to -3.47; P = 0.014). Participants in the top decile underwent their first trabeculectomy approximately 7 years earlier than participants in the lowest decile (mean difference, -7.04 years; 95% CI, 2.82-11.26). Participants in the top decile were 1.41-fold more likely to require bilateral trabeculectomy than participants in the bottom decile (odds ratio, 1.41; 95% CI, 1.06-1.91; P = 0.021).This report identified clinically relevant correlations between glaucoma PRS and the need for surgical intervention in patients with glaucoma. Further work is required to investigate the association between PRS and other clinical end points such as treatment initiation.

Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for the disease. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14 802 cases and 26 703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31 684) and brain (n = 1194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (Dataset 1: n = 73 cases and 97 controls; Dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (Dataset 1: n = 4 cases and 5 controls; Dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared with controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.

Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

PURPOSEThe exact pathogenesis of primary open-angle glaucoma (POAG) is poorly understood. Genome-wide association studies (GWAS) have recently uncovered many loci associated with variation in intraocular pressure (IOP); a crucial risk factor for POAG. Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs), the regulatory cells of IOP.METHODSSixty-two genes at fifty-five loci associated with IOP variation were knocked out in primary TMC lines. All cells underwent high-throughput microscopy imaging after being stained with a five-channel fluorescent cell staining protocol. A convolutional neural network (CNN) was trained to distinguish between gene knockout and normal control cell images. The area under the receiver operator curve (AUC) metric was used to quantify morphological variation in gene knockouts to identify potential pathological perturbations.RESULTSCells whereRALGPS1had been perturbed demonstrated the greatest morphological variation from normal TMCs (AUC 0.851, SD 0.030), followed byLTBP2(AUC 0.846, SD 0.029) andBCAS3(AUC 0.845, SD 0.020). Of seven multi-gene loci, five had statistically significant differences in AUC (pCONCLUSIONSWe demonstrate a robust method for functionally interrogating genome-wide association signals using high-throughput microscopy and AI. Genetic variations inducing marked morphological variation can be readily identified, allowing for the gene-based dissection of loci associated with complex traits.

Study ObjectivesDespite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk.MethodsWe performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (NTotal = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal = 1 477 352; Ncases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.ResultsOur SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions.ConclusionOur study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.

Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma. We evaluate the cost-effectiveness of polygenic risk score (PRS) profiling as a screening tool for POAG.We used a Markov cohort model to evaluate the cost-effectiveness of implementing PRS screening in the UK and Australia, conducted from the healthcare payer's perspective. We used published data to calculate prevalence, transition probabilities, utility, cost and other parameters in the model. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided and a 'Blindness ICER'. We did one-way as well as two-way deterministic and probabilistic sensitivity analyses.The proposed screening programme for POAG in the UK is predicted to result in ICER of £24,783 (95% CI: £13,373-66,960) and would avoid 1 year of blindness at ICER of £10,095 (95% CI: £5513-27,656). In Australia, it is predicted to result in ICER of AU$34,252 (95% CI: AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8143-37,448). Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively.We describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK for the first time and results indicated this is a promising cost-effectiveness strategy.

Purpose Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. Design Cross-sectional study. Participants Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019. Methods Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age. Main Outcome Measures Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP. Results Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4–7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61–4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3–23.6; P = 0.023). Conclusions A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.

Background The transmission dynamics and severity of coronavirus disease 2019 (COVID-19) pandemic is different across countries or regions. Differences in governments’ policy responses may explain some of these differences. We aimed to compare worldwide government responses to the spread of COVID-19, to examine the relationship between response level, response timing and the epidemic trajectory. Methods Free publicly-accessible data collected by the Coronavirus Government Response Tracker (OxCGRT) were used. Nine sub-indicators reflecting government response from 148 countries were collected systematically from January 1 to May 1, 2020. The sub-indicators were scored and were aggregated into a common Stringency Index (SI, a value between 0 and 100) that reflects the overall stringency of the government’s response in a daily basis. Group-based trajectory modelling method was used to identify trajectories of SI. Multivariable linear regression models were used to analyse the association between time to reach a high-level SI and time to the peak number of daily new cases. Results Our results identified four trajectories of response in the spread of COVID-19 based on when the response was initiated: before January 13, from January 13 to February 12, from February 12 to March 11, and the last stage—from March 11 (the day WHO declared a pandemic of COVID-19) on going. Governments’ responses were upgraded with further spread of COVID-19 but varied substantially across countries. After the adjustment of SI level, geographical region and initiation stages, each day earlier to a high SI level (SI > 80) from the start of response was associated with 0.44 (standard error: 0.08, P 2 = 0.65) days earlier to the peak number of daily new case. Also, each day earlier to a high SI level from the date of first reported case was associated with 0.65 (standard error: 0.08, P 2 = 0.42) days earlier to the peak number of daily new case. Conclusions Early start of a high-level response to COVID-19 is associated with early arrival of the peak number of daily new cases. This may help to reduce the delays in flattening the epidemic curve to the low spread level. Graphic abstract

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Summary metabolomicsR is a streamlined, flexible and user-friendly R package to preprocess, analyze and visualize metabolomic data. metabolomicsR includes comprehensive functionalities for sample and metabolite quality control, outlier detection, missing value imputation, dimensional reduction, batch effect normalization, data integration, regression, metabolite annotation and visualization of data and results. In this application note, we demonstrate the step-by-step use of the main functions from this package. Availability and implementation The metabolomicsR package is available via CRAN and GitHub (https://github.com/XikunHan/metabolomicsR/). A step-by-step online tutorial is available at https://xikunhan.github.io/metabolomicsR/docs/articles/Introduction.html. Supplementary information Supplementary data are available at Bioinformatics Advances online.

IMPORTANCE: Risk of advanced age-related macular degeneration (AAMD) is associated with rare genetic variants in the gene encoding Complement factor I (CFI), which is associated with lower circulating CFI protein levels, but the nature of the relationship is unclear. OBJECTIVE: Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk? DESIGN: Two-sample inverse variance weighted Mendelian Randomisation (MR) was used to evaluate evidence for a relationship between CFI levels and AAMD risk, comparing CFI levels from genetically predefined subsets in AAMD and control cohorts. SETTING: Published genetic and proteomic data was combined with data from cohorts of Geographic Atrophy (GA) patients in a series of MR analyses. PARTICIPANTS: We derived genetic instruments for systemic CFI level in 3,301 healthy European participants in the INTERVAL study. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, we used results from a genome-wide association study of 12,711 AAMD cases and 14,590 European controls from the International AMD Genomics Consortium (IAMDGC), and CFI levels from patients entered into the research studies SCOPE and SIGHT. RESULTS: We identified one common CFI variant rs7439493 which was strongly associated with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493 our MR analysis estimated that AAMD odds increased per standard deviation (SD) decrease in CFI level; OR 1.47 (95% confidence interval (CI) 1.30–1.65, P=2.1×10(−10)). We identified one rare variant (rs141853578 encoding p.Gly119Arg) which was genome-wide significantly associated with CFI levels after imputation; based on this, a 1 SD decrease in CFI leads to increased AAMD odds of 1.79 (95% CI 1.46–2.19, P=1.9×10(−8)). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD odds using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1 SD (3.5μg/mL) reduction in CFI was associated with 1.67 fold increased odds of AAMD (95% CI 1.40–2.00, P=1.85×10(−8)). CONCLUSION AND RELEVANCE: Excellent concordance in direction and effect size derived from rare and common variant calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.

Serum C-reactive protein (CRP), an important inflammatory marker, has been associated with age-related macular degeneration (AMD) in observational studies; however, the findings are inconsistent. It remains unclear whether the association between circulating CRP levels and AMD is causal. We used two-sample Mendelian randomization (MR) to evaluate the potential causal relationship between serum CRP levels and AMD risk. We derived genetic instruments for serum CRP levels in 418,642 participants of European ancestry from UK Biobank, and then conducted a genome-wide association study for 12,711 advanced AMD cases and 14,590 controls of European descent from the International AMD Genomics Consortium. Genetic variants which predicted elevated serum CRP levels were associated with advanced AMD (odds ratio [OR] for per standard deviation increase in serum CRP levels: 1.31, 95% confidence interval [CI]: 1.19–1.44, P = 5.2 × 10−8). The OR for the increase in advanced AMD risk when moving from low ( 3 mg/L) CRP levels is 1.29 (95% CI: 1.17–1.41). Our results were unchanged in sensitivity analyses using MR models which make different modelling assumptions. Our findings were broadly similar across the different forms of AMD (intermediate AMD, choroidal neovascularization, and geographic atrophy). We used multivariable MR to adjust for the effects of other potential AMD risk factors including smoking, body mass index, blood pressure and cholesterol; this did not alter our findings. Our study provides strong genetic evidence that higher circulating CRP levels lead to increases in risk for all forms of AMD. These findings highlight the potential utility for using circulating CRP as a biomarker in future trials aimed at modulating AMD risk via systemic therapies.

ImportanceIrreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma.ObjectiveTo assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease.Design, Setting, and ParticipantsThis cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022.Main Outcomes and MeasuresThe association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields.ResultsA total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04).Conclusions and RelevanceIn this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.

Introduction: Atherosclerosis, the main underlying causes of coronary heart disease (CHD) and ischemic stroke, is an inflammatory condition. However, therapeutics targeting inflammation for CHD and stroke are limited, partially due to insufficient evidence for causal inflammatory pathways and druggable targets. Objectives: We aimed to identify causal inflammatory markers for CHD and ischemic stroke, and to characterize the genetic architecture shared between such an inflammatory profile and CHD/stroke. Methods: Pooling multiple databases, we curated the largest genome-wide association summary statistics for 138 markers including 126 inflammatory proteins (C-reactive protein [CRP], N>450k; others such as cytokines, N~3.6k-45k) and 12 blood immune cell types (N>450k) and subsets (N~2.5k); as well as for CHD (N~547k) and stroke (N~521k). We conducted Mendelian randomization (MR) analysis using Causal Analysis Using Summary Effect Estimates and Mode-Based Estimate; and the genome-wide cross-trait meta-analysis using Association analysis based on SubSETs. Results: Of the 138 inflammatory markers, MR analyses identified 3 cellular and 4 protein markers showing significant causal effects for CHD (including white blood cell count, CD8+ T count, interleukin 6, and interleukin 22 receptor subunit alpha 1; FDR FDR APOC1-4 coregulated CHD and 5 causal markers for CHD; lead SNPs showing P FDR FDR P Conclusions: We identified cellular and protein inflammatory markers that potentially have a causal role in the development of CHD and ischemic stroke, based on genetic evidence.

Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

Importance: Early diagnosis of open-angle glaucoma can lead to vision-saving treatment, and genetic variation is an increasingly powerful indicator in disease risk stratification. Objective: To compare polygenic and monogenic variants in risk of glaucoma. Design, setting, and participants: Clinical and genetic data were obtained for 2507 individuals from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) and 411 337 individuals in cross-sectional cohort studies including individuals of European ancestry in the UK Biobank. Recruitment to the UK Biobank occurred between 2006 and 2010, and data analysis occurred between September 2019 and August 2020. Main outcomes and measures: Association of monogenic and polygenic variants with glaucoma risk. Results: Individuals at high polygenic risk, defined as those in the top 5% of an unselected population, had a glaucoma risk (odds ratio [OR], 2.77; 95% CI, 2.58-2.98) comparable with the risk among individuals heterozygous for the MYOC p.Gln368Ter variant (OR 4.19; 95% CI, 3.25-5.31), which is the most common single-gene variant known to cause primary open-angle glaucoma. High polygenic risk was more than 6 times more common than MYOC p.Gln368Ter heterozygosity in ANZRAG (15.7% vs 2.6%) and more than 15 times more common in the general population (5.0% vs 0.32%). Within ANZRAG, high polygenic risk was associated with a mean (SD) age at glaucoma diagnosis that did not differ from the age at glaucoma diagnosis among individuals heterozygous for MYOC p.Gln368Ter (57.2 [14.2] vs 54.8 [13.6] years; P > .99). Conclusions and relevance: Monogenic and high polygenic risk were each associated with a more than 2.5-fold increased odds of developing glaucoma and an equivalent mean age at glaucoma diagnosis, with high polygenic risk more than 15 times more common in the general population.

To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared to those from healthy individuals. We performed single-cell RNA-sequencing of a total of 330,569 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 2,235 significant loci across all cell types, 58 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 54 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma.

Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions., Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5–1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

Purpose: Large-scale genome-wide association studies (GWAS) have reported important single nucleotide polymorphisms (SNPs) with significant associations with age-related macular degeneration (AMD). However, their role in disease development remains elusive. This study aimed to assess SNP–metabolite associations (i.e., metabolite quantitative trait loci [met-QTL]) and to provide insights into the biological mechanisms of AMD risk SNPs. Design: Cross-sectional multicenter study (Boston, Massachusetts, and Coimbra, Portugal). Participants: Patients with AMD (n = 388) and control participants (n = 98) without any vitreoretinal disease (> 50 years). Methods: Age-related macular degeneration grading was performed using color fundus photographs according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and evaluated with mass spectrometry for metabolomic profiling and Illumina OmniExpress for SNPs profiling. Analyses of met-QTL of endogenous metabolites were conducted using linear regression models adjusted for age, gender, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. Additionally, we analyzed the cumulative effect of AMD risk SNPs on plasma metabolites by generating genetic risk scores and assessing their associations with metabolites using linear regression models, accounting for the same covariates. Modeling was performed first for each cohort, and then combined by meta-analysis. Multiple comparisons were accounted for using the false discovery rate (FDR). Main Outcome Measures: Plasma metabolite levels associated with AMD risk SNPs. Results: After quality control, data for 544 plasma metabolites were included. Meta-analysis of data from all individuals (AMD patients and control participants) identified 28 significant met-QTL (β = 0.016−0.083; FDR q-value < 1.14 × 10−2), which corresponded to 5 metabolites and 2 genes: ASPM and LIPC. Polymorphisms in the LIPC gene were associated with phosphatidylethanolamine metabolites, which are glycerophospholipids, and polymorphisms in the ASPM gene with branched-chain amino acids. Similar results were observed when considering only patients with AMD. Genetic risk score–metabolite associations further supported a global impact of AMD risk SNPs on the plasma metabolome. Conclusions: This study demonstrated that genomic–metabolomic associations can provide insights into the biological relevance of AMD risk SNPs. In particular, our results support that the LIPC gene and the glycerophospholipid metabolic pathway may play an important role in AMD, thus offering new potential therapeutic targets for this disease.

ObjectivePrimary open-angle glaucoma (POAG) is the most common subtype of glaucoma worldwide. Early diagnosis and intervention is proven to slow disease progression and reduce disease burden. Currently, population-based screening for POAG is not generally recommended due to cost. In this study, we evaluate the cost-effectiveness of polygenic risk profiling as a screening tool for POAG.Methods and AnalysisWe used a Markov cohort model to evaluate the cost-effectiveness of implementing polygenic risk profiling as a new POAG-screening approach in the UK and Australia. Six health states were included in this model: death, early, mild, moderate, severe, and healthy individuals. The evaluation was conducted from the healthcare payer’s perspective. We used the best available published data to calculate prevalence, transition probabilities, utility and other parameters for each health state and age group. The study followed the CHEERS checklist. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided per person and a ‘Blindness ICER’. We did one-way and two-way deterministic and probabilistic sensitivity analyses to reflect the uncertainty around predicting ICERs.ResultsOur proposed genetic screening programme for POAG in Australia is predicted to result in ICER of AU$34,252 (95% CI AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8,143-37,448). In the UK, this screening is predicted to result in ICER of £24,783 (13,373-66,960) and would avoid 1 year of blindness at ICER of £10,095 (95%CI: £5,513-27,656). Findings were robust in all sensitivity analyses. Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively.ConclusionsWe describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK. Although the level of willingness to pay for Australian Government is uncertain, and the ICER range for the UK is broad, we showed a clear target strategy for early detection and prevention of advanced POAG in these developed countries.Copyrightthe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence.

Background: Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma worldwide. We evaluate the cost-effectiveness of polygenic risk score (PRS) profiling as a screening tool for POAG. Methods: We used a Markov cohort model to evaluate the cost-effectiveness of implementing PRS screening in the UK and Australia, conducted from the healthcare payer’s perspective. We used published data to calculate prevalence, transition probabilities, utility and other parameters for each health state and age group. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided and a ‘Blindness ICER’. We did one-way as well as two-way deterministic and probabilistic sensitivity analyses. Results: Our proposed genetic screening programme for POAG in Australia is predicted to result in ICER of AU$34,252 (95% CI AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8,143-37,448). In the UK, this screening is predicted to result in ICER of £24,783 (13,373-66,960) and would avoid 1 year of blindness at ICER of £10,095 (95%CI: £5,513-27,656). Findings were robust in all sensitivity analyses. Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively. Interpretation: We describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK for the first time and results indicated this is a promising cost-effectiveness strategy. Funding Statement: We had funding from a NHMRC Program grant (1150144), Partnership grant (1132454) and a Centre for Research Excellence grant (1116360). Declaration of Interests: S.M., J.E.C., and A.W.H. are listed as co-inventors on a patent application (WO2019241844A1) for the use of genetic risk scores to determine risk and guide treatment for glaucoma.

Background: Observational studies have suggested that individuals with pre-existing sleep apnoea (SA) have up to double the risk of developing glaucoma than individuals without SA. However, it is unclear if these associations are due to confounding or reverse causation. Disentangling causality from confounding is essential to further our understanding of both diseases. Mendelian randomisation (MR) techniques, which use genetic variants associated with a risk factor (e.g. SA) as instrumental variables (IVs), can be used to infer causality. MR methods can be less susceptible to confounders or reverse causation than observational studies. Methods: In this study, 34 IVs for SA were derived from a genome-wide association study (GWAS) of 25 008 SA cases, 313 372 controls. Two Sample MR analyses were performed to evaluate the relationship between genetically predicted SA and glaucoma susceptibility using summary data from a glaucoma GWAS meta-analysis (20 582 cases, 119 318 controls). We derived odds ratios (OR) for glaucoma arising from a doubling in the genetic odds of having SA. Finding: Using 34 SA SNPs as IVs, we found no strong evidence for an association between SA susceptibility and glaucoma (OR = 0.95, 95% confidence intervals = 0.77 - 1.13) based on the inverse variance weighted (IVW) MR estimator. Interpretation: We found little genetic evidence supporting a causal association between SA and glaucoma. Our results refute the possibility of a large effect (glaucoma OR > 1.5 per doubling of odds on SA) between SA and glaucoma. Funding Information: S.M. and D.A.M are supported by the Australian National Health and Medical Research Council (NHMRC) Fellowships. X.H. is supported by the University of Queensland Research Training Scholarship and QIMR Berghofer Medical Research Institute PhD Top Up Scholarship. We acknowledge funding from NHMRC grants 1123248, 1116360, 1150144, 1023911. A.I.C. is supported by a UQ Research Training Scholarship from The University of Queensland (UQ). M.E.R. acknowledges support from the NHMRC and Australian Research Council (ARC) through a Research Fellowship (GNT1102821). Declaration of Interests: There are no competing interest to disclose. Ethics Approval Statement: Both sources of GWAS summary statistics included here acquired appropriate ethical approval. No ethical approval was required for this study.

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time-intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach we perform a systematic comparison of the distribution of VCDR and VDD, and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI based gradings increased estimates of heritability by ~50% for VCDR and VDD. Our GWAS identified more than 200 loci for both VCDR and VDD (double the number of loci from previous studies), uncovers dozens of novel biological pathways, with many of the novel loci also conferring risk for glaucoma.

BackgroundSleep apnoea is characterised by periods of halted breathing during sleep. Despite its association with severe health conditions, the aetiology of sleep apnoea remains understudied, and previous genetic analyses have not identified many robustly associated genetic risk variants.MethodsWe performed a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts (NTotal=523,366), followed by a multi-trait analysis of GWAS (MTAG) to boost power, leveraging the high genetic correlation between sleep apnoea and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional & joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal=1,477,352; Ncases=175,522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.ResultsOur MTAG analysis uncovered 49 significant independent loci associated with sleep apnoea risk. Twenty-nine variants were replicated in the 23andMe cohort. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions.ConclusionsOur study uncovered multiple genetic loci associated with sleep apnoea risk, thus increasing our understanding of the aetiology of this condition and its relationship with other complex traits.

Background Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear. Methods Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64–407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium. Results Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. Conclusion These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.

In late May, the World Health Organization (WHO) declared that the Americas have now become the epicentre of the global coronavirus disease 2019 (COVID-19) pandemic, with Latin America having passed Europe and the USA in number of daily confirmed cases. Within Latin America, Brazil is currently taking the lead with the highest number of cases and deaths in the region. Although COVID-19 is a growing ongoing issue in Brazil, Brazilian president Jair Bolsonaro does not seem very concerned with this major public health problem, having said 'So what?', when asked about the rapidly growing number of COVID-19 cases in the country..

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible., Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification.DESIGN: Cross-sectional study.PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients.METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group.MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity.RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01).CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.