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.
We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer's disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide 1,2 . The disease is characterized by progressive optic nerve degeneration that is usually accompanied by elevated intraocular pressure (IOP). Neuroprotective therapies are not available and current treatments are limited to lowering IOP which can slow disease progression at early disease stages. However over 50% of glaucoma is not diagnosed until irreversible optic nerve damage has occurred 2,3 .
Background: Keratinocyte cancer (KC) is the commonest cancer, imposing a high economic burden on the healthcare system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFAs) and KC; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). We explored if genetically predicted PUFA levels are associated with BCC and SCC risks.
Methods:We conducted a two sample Mendelian Randomisation study using PUFA level GWASs from the CHARGE consortium (n > 8,000), and the meta-analysis GWASs from UKB, 23andMe and Qskin for BCC (n=651,138) and SCC (n= 635,331) risk.Results: One standard deviation increase in genetically predicted levels of linoleic acid (OR = 0.94, 95% CI = 0.91-0.97, P = 1.4 × 10 -4 ) and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86-0.96, P = 5.1 × 10 -4 ) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02-1.06, P = 3.2 × 10 -4 ) and eicosapentaenoic acid (OR=1.10, 95% CI = 1.04-1.16, P = 1.5 × 10 -3 ) were associated with an increased BCC risk.
Conclusion:Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk.
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The introduction chapter (Chapter 1) starts with a summary of recent progress in genetic epidemiology. The advancement of genotyping technology made it feasible to revisit a 30 years old study design known as Mendelian randomization (MR) where germline genetic variants can be used as natural instruments to assess causality between human complex traits. Here the rationale and technical assumptions required to conduct feasible MR studies were explained. The overall thesis objective and study approaches used in the thesis were also outlined. The final subchapter provides details on the definition of disease phenotypes that will be used throughout the thesis, including the creation of a "pan-cancer" phenotype, a combined cancer outcome of whether a person is diagnosed with any cancer, which was subsequently used in Chapter 4 and 5.In Chapters 2 and 3, I investigated whether MR can be used to infer causality between modifiable risk factors and specific cancers. For Chapter 2, I applied MR to evaluate the link between vitamin D and coffee intake on epithelial ovarian carcinomas (EOC). This was done in a two-sample MR framework where genetic instruments for the risk factor were obtained from public GWAS literature and the cancer GWAS statistics were obtained from the Ovarian Cancer Association Consortium (OCAC). While higher genetically predicted vitamin D reduced the risk of EOC, there was no evidence to support a link between genetically predicted coffee intake and EOC. For Chapter 3, I contrasted and compared the association between alcohol intake with breast and ovarian cancer using both MR and observational analyses. Genetic summary statistics were obtained from the OCAC and BCAC (breast cancer). Previous observational findings show an adverse relationship between alcohol intake and breast cancer susceptibility, however the association was protective on EOC. Our observational data replicate previous findings, with MR estimates showing consistent direction of effect for EOC; while no evidence to support a strong link between alcohol intake and breast cancer risk. Taken altogether, the effect of alcohol on these cancers is likely small if causative at all.In Chapter 4 and 5, I performed MR to evaluate a series of modifiable risk factors on overall cancer outcomes. Using data from the UK Biobank, we constructed an aggregate phenotype allowing us to evaluate whether "modifying specific behaviour (or risk factor) will 3 alter an individual's risk of being diagnosed or dying from cancer". The proof-of-principle MR study using height is shown in Chapter 4, where MR findings are highly concordant with observational findings that taller people have increased risk of developing cancer. Findings for obesity, vitamin D and coffee intake on overall cancer outcomes are further elaborated in Chapter 5.In Chapter 5, the approach undertaken to evaluate these risk factors and cancer were each described in turn, followed by a subchapter to summarise these MR findings. Genetically higher BMI is associated with an increase of being dia...
Cholesterol-lowering genetic variants are not associated with the risk of skin cancer
Dear EditorThe incidence of skin cancer is high in white-skinned populations and has been rising over the past 3-4 decades. 1 Control efforts have focused on primary prevention, but chemoprevention could be used as an adjunct to sun protection measures if suitable agents were shown to be effective. Low-density lipoprotein-cholesterol (LDL-C)-lowering drugs have shown chemopreventive activity against some
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