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Background and Objectives: Until 25 July 2022, people who spent more than 6 months in the United Kingdom during the variant Creutzfeldt–Jakob disease (vCJD) risk period 1980–1996 (UK donors) were deferred from blood donation in Australia. Regulatory approval to remove the deferral was underpinned by published mathematical modelling predicting negligible vCJD transmission risk increase with a gain of 58,000 donations. Materials and Methods: The donor questionnaire retained the UK deferral screening question until a version update effective 12 February 2023, which enabled identification of the newly eligible cohort of UK donors. Their donations were tracked for a 6‐month period (25 July 2022–24 January 2023) and compared with baseline Lifeblood donation metrics and predicted gains. Results: A total of 38,462 UK donors attended to donate 78,762 times in the 6 months. Of these, 32,358 donors (females = 19,456, males = 12,902) successfully donated 67,914 times representing 8.4% of total collections. Conclusion: Cessation of the UK deferral resulted in donation gains exceeding modelled predictions because of a higher than predicted number of donors who donated at a higher rate. Had these newly eligible donors not donated, overall donation numbers would have been 88% of target rather than the 96% achieved. [ABSTRACT FROM AUTHOR]

Background and Objectives: Most of the 233 worldwide cases of variant Creutzfeldt–Jakob disease (vCJD) have been reported in the United Kingdom and 3 have been associated with transfusion‐transmission. To mitigate the potential vCJD risk to blood safety, Australian Red Cross Lifeblood imposes restrictions on blood donation from people with prior residency in, or extended travel to, the United Kingdom during the risk period 1980–1996. We have modified a previously published methodology to estimate the transfusion‐transmission risk of vCJD associated with fresh component transfusion in Australia if the UK residence deferral was removed. Materials and Methods: The prevalence of current pre‐symptomatic vCJD infection in the United Kingdom by age at infection and genotype was estimated based on risk of exposure to the bovine spongiform encephalopathy agent for the period 1980–1996. These results were used to estimate the age‐specific prevalence of undiagnosed, pre‐symptomatic vCJD in the Australian population in the current year due to prior UK residency or travel. The primary model outputs were the 2020 vCJD risks/unit of vCJD contamination, transfusion‐transmission (infections) and clinical cases. Results: The overall (prior UK residency in and travel to United Kingdom, 1980–1996) mean risk of contamination per unit was 1 in 29,900,000. The risks of resulting vCJD transmission (infection) and clinical case were 1 in 389,000,000 and 1 in 1,450,000,000, respectively. Conclusion: Our modelling suggests that removing the Lifeblood donation deferral for travel to, or UK residence, would result in virtually no increased risk of vCJD transfusion‐transmission and would be a safe and effective strategy for increasing the donor base. [ABSTRACT FROM AUTHOR]

Summary: Background: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS‐based risk prediction, particularly assessment of calibration (comparing predicted to observed risks). Objectives: To evaluate PRS‐based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. Methods: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case‐cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single‐nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta‐analysis (PRS68), 50 SNPs significant in the 2020 meta‐analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten‐year melanoma risks were calculated from population‐level cancer registry data by age group and sex, with and without PRS adjustment. Results: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62–0·68] and MCCS (E/O = 0·63, 95% CI 0·56–0·72). For UKB, calibration was improved by PRS adjustment, with PRS50‐adjusted risks E/O = 0·91, 95% CI 0·87–0·95. The discriminative ability for PRS68‐ and PRS50‐adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07–0·10, P < 0·0001), and higher than for PRS45‐adjusted risks (Δ area under the curve 0·02–0·04, P < 0·001). Conclusions: A PRS derived from a larger, more diverse meta‐analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations. [ABSTRACT FROM AUTHOR]

Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk‐marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual‐level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29‐1.55; QSkin OR 1.58, 95% CI: 1.29‐1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33‐1.44; QSkin OR 1.20, 95% CI: 1.05‐1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28‐1.55; QSkin OR 1.44, 95% CI: 1.19‐1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have suggested that coffee intake may be associated with a reduction in cancer risk. Mendelian randomization (MR) studies can help clarify whether the observed associations are likely to be causal. Here we evaluated whether coffee intake is associated with: (i) overall risk of being diagnosed with/dying from any cancer; and (ii) risk of individual cancers.Methods: We identified 46 155 cases (of which 6998 were fatal) and 270 342 controls of White British ancestry from the UK Biobank cohort (UKB), based on ICD10 diagnoses. Individuals with benign tumours were excluded. Coffee intake was self-reported and recorded based on cup/day consumption. We conducted both observational and summary data MR analyses.Results: There was no observational association between coffee intake and overall cancer risk [odds ratio (OR) per one cup/day increase = 0.99, 95% confidence interval (CI) 0.98, 1.00] or cancer death (OR = 1.01, 0.99, 1.03); the estimated OR from MR is 1.01 (0.94, 1.08) for overall cancer risk and 1.11 (0.95, 1.31) for cancer death. The relationship between coffee intake and individual cancer risks were consistent with a null effect, with most cancers showing little or no associations with coffee. Meta-analysis of our MR findings with publicly available summary data on various cancers do not support a strong causal relationship between coffee and risk of breast, ovarian, lung or prostate cancer, upon correction for multiple testing.Conclusions: Taken together, coffee intake is not associated with overall risk of being diagnosed with or dying from cancer in UKB. For individual cancers, our findings were not statistically inconsistent with earlier observational studies, although for these we were unable to rule out a small effect on specific types of cancer. [ABSTRACT FROM AUTHOR]

Abstract: It has consistently been reported that patients with schizophrenia have an increased risk of type-2 diabetes. To investigate a genetic link between these two diseases, the combined effects of the PLA2G4A, PTGS2 and PPARG genes were tested among 221 British nuclear families consisting of fathers, mothers and affected offspring with schizophrenia. A total of 10 single nucleotide polymorphisms (SNPs) were tested and the likelihood-based association analysis for nuclear families was used to analyse the genotyping data. Eight SNPs detected across the PPARG gene did not show allelic association with schizophrenia; a weak association was detected at rs2745557 in the PTGS2 locus (χ 2=4.19, p=0.041) and rs10798059 in the PLA2G4A locus (χ 2=4.28, p=0.039) but these associations did not survive after 10,000 permutations to correct the p-value (global p=0.246). The gene–gene interaction test did not show any evidence of either cis-phase interactions for the PLA2G4A and PTGS2 combinations or a trans-phase interaction for the PLA2G4A and PPARG combinations. The PPARG gene has been reported to be strongly associated with type-2 diabetes, but the present study did not support the hypothesis that the PPARG gene may also play an important role in the development of schizophrenia. [Copyright &y& Elsevier]

Background To improve melanoma early detection, tools to predict personal risk based on genetic information (polygenic risk scores, PRS) have been developed, but require external validation. Methods We analysed invasive melanoma incidence in UK Biobank (UKB; n = 395,647; 1,651 cases) and the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4,765; 303 cases). Three PRS were evaluated: 68 genetic variants (SNPs) at 54 loci from a 2020 meta-analysis (PRS68); 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50); 45 SNPs at 21 loci known pre-2020 (PRS45). 10-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. Results All PRS were strongly associated with melanoma incidence, including after adjustment for age, sex, ethnicity, and ease of tanning. Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in UKB (ratio expected/observed cases E/O=0.65, 95% confidence interval 0.62-0.68) and MCCS (E/O=0.65, 0.57-0.73). For UKB, this was reduced by PRS-adjustment, e.g. PRS50-adjusted risks E/O=0.91 (0.87-0.95). Discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (deltaAUC 0.07-0.1, p < 0.0001), and higher than for PRS45-adjusted risks (deltaAUC 0.02-0.04, p < 0.001). Conclusions A PRS derived from a larger, more diverse meta-analysis improves melanoma risk prediction compared to an earlier PRS. Re-calibration of absolute risks may be necessary for application to specific populations. Key messages A genetic score can improve prediction of melanoma risk and might help tailor melanoma prevention and early detection strategies to different risk levels. [ABSTRACT FROM AUTHOR]

Background A personal history of keratinocyte carcinoma (KC) has been reported as a risk factor for developing subsequent primary cutaneous and non-cutaneous malignancies. However most evidence to date stems from observational studies which are prone to bias, confounding and reverse causation. Our aim was to examine this association using different Mendelian randomization (MR) approaches. Methods We performed a one-sample MR analysis using individual-level data from the UK Biobank (n = 394,306). This analysis was then validated in an independent dataset in the QSkin cohort (n = 16,896). Using 64 independent genetic variants known to be associated with KC, we generated a polygenic risk score (PRS) for each participant in the UK Biobank and the QSkin cohort. We then performed two-sample MR analyses using genome-wide association study (GWAS) summary statistics. We tested the association between genetically predicted KC and risk of subsequent cancer using logistic regression. Results Results from one-sample MR analyses in the UK Biobank indicated that a personal history of KC was significantly associated with cancer overall (excluding melanoma) (OR: 1.15, 95% CI: 1.10-1.20, per doubling the prevalence of KC). The results from the two-sample MR corroborate the findings from the one-sample MR, although the risk estimate was lower (OR: 1.05, 95% CI: 1.03-1.07). Conclusions Our MR analyses suggest that genetically predicted KC is a risk factor for developing subsequent primary malignancies. Key messages A personal history of KC may serve as a proxy marker of inherited cancer risk. [ABSTRACT FROM AUTHOR]

Background: Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks., Methods: We conducted a two-sample Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology 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 SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (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., Conclusions: 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., Impact: PUFA-related diet and supplementation could influence BCC etiology., (©2021 The Authors; Published by the American Association for Cancer Research.)

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10 - 6 ). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Background: Observational studies evaluating the link between polyunsaturated fatty acids (PUFA) and cancers have yielded mixed findings. We used Mendelian randomization (MR) to evaluate whether genetic evidence supports a causal role for PUFAs on overall cancer outcomes., Methods: We identified genetic instruments for six PUFAs from previous literature and evaluated their association with overall cancer risk (46,155 cases, 270,342 controls) and cancer mortality (6,998 deaths, 270,342 controls) among the UK Biobank cohort. We used the inverse variance weighted model to combine SNP estimates, and derived log (OR) estimates per SD change in each PUFA., Results: None of the six PUFAs showed association with overall cancer risk or mortality, with narrow confidence interval (CI) ruling out all but very small effects, for example, arachidonic acid (AA) overall cancer risk (OR, 1.02; 95% CI, 1.00-1.03). Sex-specific analysis revealed no associations except α-linolenic acid for potentially reducing cancer risk in men (OR, 0.92; 95% CI, 0.86-0.98; P = 0.02); however, this was nonsignificant after multiple testing correction. From individual cancers, only colorectal cancer showed evidence for a causal association for higher AA levels (OR, 1.05; 95% CI, 1.03-1.07), with similar results for the other correlated PUFAs., Conclusions: Our study provides no support for the hypothesis that PUFAs reduce overall cancer risk or mortality. Higher AA levels increased the risk for colorectal cancer., Impact: Our well-powered MR study provides robust causal inferences for the PUFAs on overall cancer risk and mortality. Future larger studies are warranted to replicate the individual cancer findings., (©2019 American Association for Cancer Research.)

Background: 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'., Methods: 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., Results: 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., Conclusions: 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.

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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)., Results: 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., Conclusions: 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.

Several lines of evidence have suggested an interesting link between gluten ingestion and schizophrenia. Increased levels of gliadin antibodies have been observed in patients with schizophrenia. Tissue transglutaminase (transglutaminase 2, TGM2) is involved in the production of gliadin antibodies. To investigate genetic association of the TGM2 gene with schizophrenia, we detected eight single nucleotide polymorphisms (SNPs) present in the gene among 131 family trios composed of fathers, mothers and affected offspring with schizophrenia. Data analysis with the UNPHASED program showed allelic association for rs2076380 (chi(2) = 5.51, P = 0.019), rs7270785 (chi(2) = 8.13, P = 0.004), rs4811528 (chi(2) = 6.13, P = 0.013) and rs6023526 (chi(2) = 6.13, P = 0.013). The global P-value was 0.029 for 10,000 permutations with the TDT analysis. The strongest association was observed for the rs7270785-rs4811528 haplotypes (chi(2) = 16.18, df = 3, P = 0.001), and the global P-value was 0.008 for 10,000 permutations with the 2-SNP haplotype analysis. The 8-SNP haplotype analysis also revealed a strong haplotypic association (chi(2) = 44.82, df = 18, P = 0.0004) and the 1-df test showed that the A-T-A-A-T-G-A-G haplotype was excessively transmitted (chi(2) = 16.98, corrected P = 0.0007). The present results suggest that the TGM2 gene may be involved in the development of schizophrenia., ((c) 2008 Wiley-Liss, Inc.)