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) to high (> 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.
Abstract
There is considerable debate regarding the role that 25-hydroxyvitamin D 25(OH)D concentrations play in cancer risk or mortality, with earlier studies drawing mixed conclusions. Using data ...from the UK Biobank (UKB), we evaluate whether genetically predicted 25(OH)D concentrations are associated with overall cancer susceptibility and cancer mortality using five 25(OH)D genetic markers. Data comprised 438 870 white British UKB participants aged 37-73, including 46 155 cancer cases and 6998 cancer-specific deaths. Participants with keratinocyte cancers and/or benign tumors were excluded from the analysis. Odds ratios were calculated per 20 nmol/L increase in genetically predicted 25(OH)D for cancer risk and cancer mortality. For individual cancer risks, estimates were meta-analyzed with publicly available data using a fixed-effect inverse-variance-weighted model. We demonstrated that genetically low plasma 25(OH)D concentrations were not associated with increased cancer risk nor cancer mortality. Stratification by sex or cancer types did not reveal any meaningful differences albeit wider confidence intervals. Fixed-effect meta-analysis of our individual cancer risk estimates with those derived from publicly available cancer consortia data and previous studies further reinforced our null Mendelian randomization findings on prostate, lung, colorectal and breast cancers with tight confidence intervals; for ovarian and pancreatic cancers, our estimates were less precise despite being not statistically significant. Taken altogether, our results provide no genetic evidence for an association between vitamin D and overall cancer outcomes, with tight confidence intervals to exclude all but very small effect sizes.
Background/aimsRecent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG ...than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry.MethodsThe authors completed a case–control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly sampled from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of <11/22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores.ResultsA total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2; 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108).ConclusionThis study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.
Observational studies have shown that being taller is associated with greater cancer risk. However, the interpretation of such studies can be hampered by important issues such as confounding and ...reporting bias.
We used the UK Biobank resource to develop genetic predictors of height and applied these in a Mendelian randomisation framework to estimate the causal relationship between height and cancer. Up to 438,870 UK Biobank participants were considered in our analysis. We addressed two primary cancer outcomes, cancer incidence by age ~60 and cancer mortality by age ~60 (where age ~60 is the typical age of UK Biobank participants).
We found that each genetically predicted 9 cm increase in height conferred an odds ratio of 1.10 (95% confidence interval 1.07-1.13) and 1.09 (1.02-1.16) for diagnosis of any cancer and death from any cancer, respectively. For both risk and mortality, the effect was larger in females than in males.
Height increases the risk of being diagnosed with and dying from cancer. These findings from Mendelian randomisation analyses agree with observational studies and provide evidence that they were not likely to have been strongly affected by confounding or reporting bias.
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.
Whether body mass index (BMI) is causally associated with the risk of being diagnosed with or dying from any cancer remains unclear. Weight reduction has clinical importance for cancer control only ...if weight gain causes cancer development or death. We aimed to answer the question 'does genetically predicted BMI influence my risk of being diagnosed with or dying from any cancer'.
We used a Mendelian randomisation (MR) approach to estimate causal effect of BMI in 46,155 white-British participants aged between 40 and 69 years at recruitment (median age at follow-up 61 years) from the UK Biobank, who developed any type of cancer, among whom 6998 died from cancer. To derive MR instruments for BMI, we selected up to 390,628 cancer-free participants.
For each standard deviation (4.78 units) increase in genetically predicted BMI, we estimated a causal odds ratio (COR) of 1.07 (1.02-1.12) and 1.28 (1.16-1.41) for overall cancer risk and mortality, respectively. The corresponding estimates were similar for males and females, and smokers and non-smokers.
Higher genetically predicted BMI increases the risk of being diagnosed with or dying from any cancer. These data suggest that increased overall weight may causally increase overall cancer incidence and mortality among Europeans.
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.
Cross-sectional study.
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.
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.
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.
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).
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.
Consumption of coffee, tea and alcohol might be shaped by individual differences in bitter taste perception but inconsistent observational findings provide little insight regarding causality. We ...conducted Mendelian randomization analyses using genetic variants associated with the perception of bitter substances (rs1726866 for propylthiouracil PROP, rs10772420 for quinine and rs2597979 for caffeine) to evaluate the intake of coffee, tea and alcohol among up to 438,870 UK Biobank participants. A standard deviation (SD) higher in genetically predicted bitterness of caffeine was associated with increased coffee intake (0.146 95%CI: 0.103, 0.189 cups/day), whereas a SD higher in those of PROP and quinine was associated with decreased coffee intake (-0.021 -0.031, -0.011 and -0.081 -0.108, -0.054 cups/day respectively). Higher caffeine perception was also associated with increased risk of being a heavy (>4 cups/day) coffee drinker (OR 1.207 1.126, 1.294). Opposite pattern of associations was observed for tea possibly due to the inverse relationship between both beverages. Alcohol intake was only negatively associated with PROP perception (-0.141 -1.88, -0.94 times/month per SD increase in PROP bitterness). Our results reveal that bitter perception is causally associated with intake of coffee, tea and alcohol, suggesting a role of bitter taste in the development of bitter beverage consumption.
Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an ...increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome‐wide association study (GWAS) meta‐analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta‐analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark “large” predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17th percentile to the median. Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk: odds ratio OR = 1.03 (95% confidence interval CI = 0.96–1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small.
What's new?
Studies have indicated that dietary interventions might be able to reduce melanoma risk. The Mediterranean diet, which includes ample intake of polyunsaturated fatty acids (PUFAs), has shown particular promise. In this statistical analysis, the authors used a technique called Mendelian randomisation, in which certain SNPs are associated with a particular variable e.g. PUFA, to assess whether PUFA levels affect melanoma risk. Their results indicate that the impact of dietary PUFAs is negligible. Further studies are thus needed to explore whether other components of the Mediterranean diet might reduce melanoma risk.
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