Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Genetic variants for smoking behaviour and risk of skin cancer.

Observational studies have suggested that smoking may increase the risk of cutaneous squamous cell carcinoma (cSCC) while decreasing the risks of basal cell carcinoma (BCC), and melanoma. However, it remains possible that confounding by other factors may explain these associations. The aim of this investigation was to use Mendelian randomization (MR) to test whether smoking is associated with skin cancer, independently of other factors. Two-sample MR analyses were conducted to determine the causal effect of smoking measures on skin cancer risk using genome-wide association study (GWAS) summary statistics. We used the inverse-variance-weighted estimator to derive separate risk estimates across genetic instruments for all smoking measures. A genetic predisposition to smoking initiation was associated with lower risks of all skin cancer types, although none of the effect estimates reached statistical significance (OR 95% CI BCC 0.91, 0.82-1.01; cSCC 0.82, 0.66-1.01; melanoma 0.91, 0.82-1.01). Results for other measures were similar to smoking initiation with the exception of smoking intensity which was associated with a significantly reduced risk of melanoma (OR 0.67, 95% CI 0.51-0.89). Our findings support the findings of observational studies linking smoking to lower risks of melanoma and BCC. However, we found no evidence that smoking is associated with an elevated risk of cSCC; indeed, our results are most consistent with a decreased risk, similar to BCC and melanoma.

Uncovering the complex relationship between balding, testosterone and skin cancers in men.

Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, and multivariable models revealed that this relationship was heavily confounded by MPB single nucleotide polymorphisms involved in pigmentation pathways. Site-stratified MR analyses revealed strong associations between MPB with head and neck squamous cell carcinoma and melanoma, suggesting that sun exposure on the scalp, rather than androgens, is the main driver. Men with less hair covering likely explains, at least in part, the higher incidence of melanoma in men residing in countries with high ambient UV.

Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort.

Introduction: Gestational diabetes mellitus (GDM) is the most common pregnancy complication worldwide and is associated with short- and long-term health implications for both mother and child. Prevalence of GDM varies between ethnicities, with South Asians (SAs) experiencing up to three times the risk compared to white Europeans (WEs). Recent evidence suggests that underlying metabolic difference contribute to this disparity, but an investigation of causality is required. Methods: To address this, we paired metabolite and genomic data to evaluate the causal effect of 146 distinct metabolic characteristics on gestational dysglycemia in SAs and WEs. First, we performed 292 GWASs to identify ethnic-specific genetic variants associated with each metabolite (P ≤ 1 x 10-5) in the Born and Bradford cohort (3688 SA and 3354 WE women). Following this, a one-sample Mendelian Randomisation (MR) approach was applied for each metabolite against fasting glucose and 2-hr post glucose at 26-28 weeks gestation. Additional GWAS and MR on 22 composite measures of metabolite classes were also conducted. Results: This study identified 15 novel genome-wide significant (GWS) SNPs associated with tyrosine in the FOXN and SLC13A2 genes and 1 novel GWS SNP (currently in no known gene) associated with acetate in SAs. Using MR approach, 14 metabolites were found to be associated with postprandial glucose in WEs, while in SAs a distinct panel of 11 metabolites were identified. Interestingly, in WEs, cholesterols were the dominant metabolite class driving with dysglycemia, while in SAs saturated fatty acids and total fatty acids were most commonly associated with dysglycemia. Discussion: In summary, we confirm and demonstrate the presence of ethnic-specific causal relationships between metabolites and dysglycemia in mid-pregnancy in a UK population of SA and WE pregnant women. Future work will aim to investigate their biological mechanisms on dysglycemia and translating this work towards ethnically tailored GDM prevention strategies.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions.

BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). CONCLUSIONS: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Somatostatin Receptor PET/MR Imaging of Inflammation in Patients With Large Vessel Vasculitis and Atherosclerosis.

BACKGROUND: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures. OBJECTIVES: We aimed to investigate somatostatin receptor 2 (SST2) as a novel inflammation-specific molecular imaging target in LVV. METHODS: In a prospective, observational cohort study, in vivo arterial SST2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68Ga-DOTATATE and 18F-FET-ßAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing. RESULTS: Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST2 maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST2 signal was not elevated in any of the control subjects. SST2 PET/MRI was generally consistent with 18F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers. CONCLUSIONS: SST2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA], NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE], NCT04073810).

Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort.

Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 coding variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.

Massively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity.

The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRAs) by using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRAs, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%). We further characterized MPRA-significant variants by motif prediction, epigenomic annotation, and statistical/functional fine-mapping to create integrative variant scores, which prioritized one to six plausible candidate variants per locus for the 42 loci and nominated a single variant for 43% of these loci. Overlaying the MPRA-significant variants with genome-wide significant expression or methylation quantitative trait loci (eQTLs or meQTLs, respectively) from melanocytes or melanomas identified candidate susceptibility genes for 60% of variants (172 of 285 variants). CRISPRi of top-scoring variants validated their cis-regulatory effect on the eQTL target genes, MAFF (22q13.1) and GPRC5A (12p13.1). Finally, we identified 36 melanoma-specific and 45 melanocyte-specific MPRA-significant variants, a subset of which are linked to cell-type-specific target genes. Analyses of transcription factor availability in MPRA datasets and variant-transcription-factor interaction in eQTL datasets highlighted the roles of transcription factors in cell-type-specific variant functionality. In conclusion, MPRAs along with variant scoring effectively prioritized plausible candidates for most melanoma GWAS loci and highlighted cellular contexts where the susceptibility variants are functional.

Differences in the management of patients requiring an emergency resection for colonic cancer in two European populations.

BACKGROUND: Patients with colonic cancer who require emergency colonic cancer surgery often experience poorer outcomes compared with their elective counterparts. In this setting, several treatments approaches are available. In 2009, Danish guidelines recommended treatment with stent for obstruction in left-sided tumours as a bridge to surgery, if expertise is accessible. The aim of this study was to compare the use of elective and emergency resections for colonic cancer and postoperative mortality in two similar demographic populations. METHODS: All patients who underwent a major resection for colonic cancer, between 2005 and 2016 in Denmark and Yorkshire (UK) were identified. The proportion undergoing emergency surgery, the proportion receiving a stent procedure before their resection, and 30-day postoperative mortality were compared between the populations. Logistic regression was used to determine changes in the proportion of those undergoing emergency surgery and 30-day postoperative mortality. RESULTS: Out of 45 397 patients treated during the study interval, 41 880 were selected. Emergency surgery decreased in Denmark from 16.6 per cent in 2005-07 to 12.9 per cent in 2014-16, but increased in Yorkshire (13.5 per cent to 16.8 per cent). Danish patients with left-sided tumours were less likely to undergo emergency surgery (risk ratio 0.90, 95 per cent c.i. 0.82 to 0.99) and an increase in stent use coincided with a statistically significant decrease in emergency surgery in these patients. Thirty-day postoperative mortality in all resections (elective and emergency) decreased in both populations, but a larger decrease was observed in Denmark (7.7 per cent to 3.0 per cent in Denmark and 7.1 per cent to 3.3 per cent in Yorkshire). CONCLUSION: Patients in Denmark experienced a reduction in the use of emergency resection and increase in stenting procedures, following the policy implemented in some departments of converting potential emergency resections into elective resections.

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting.

BACKGROUND: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. OBJECTIVE: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. METHODS: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. RESULTS: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61-2.71, P = 2.08 × 10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77-3.21, P = 1.07 × 10-8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83-0.94, P = 6.93 × 10-5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90). CONCLUSION: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

Unique Metabolic Profiles Associate with Gestational Diabetes and Ethnicity in Low- and High-Risk Women Living in the UK.

BACKGROUND: Gestational diabetes mellitus (GDM) is the most common global pregnancy complication; however, prevalence varies substantially between ethnicities, with South Asians (SAs) experiencing up to 3 times the risk of the disease compared with white Europeans (WEs). Factors driving this discrepancy are unclear, although the metabolome is of great interest as GDM is known to be characterized by metabolic dysregulation. OBJECTIVES: The primary aim was to characterize and compare the metabolic profiles of GDM in SA and WE women (at <28 wk of gestation) from the Born in Bradford (BIB) prospective birth cohort in the United Kingdom. METHODS: In total, 146 fasting serum metabolites, from 2,668 pregnant WE and 2,671 pregnant SA women (average BMI 26.2 kg/m2, average age 27.3 y) were analyzed using partial least squares discriminatory analyses to characterize GDM status. Linear associations between metabolite values and post-oral glucose tolerance test measures of dysglycemia (fasting glucose and 2 h postglucose) were also examined. RESULTS: Seven metabolites associated with GDM status in both ethnicities (variable importance in projection ≥1), whereas 6 additional metabolites associated with GDM only in WE women. Unique metabolic profiles were observed in healthy-weight women who later developed GDM, with distinct metabolite patterns identified by ethnicity and BMI status. Of the metabolite values analyzed in relation to dysglycemia, lactate, histidine, apolipoprotein A1, HDL cholesterol, and HDL2 cholesterol associated with decreased glucose concentration, whereas DHA and the diameter of very low-density lipoprotein particles (nm) associated with increased glucose concertation in WE women, and in SAs, albumin alone associated with decreased glucose concentration. CONCLUSIONS: This study shows that the metabolic risk profile for GDM differs between WE and SA women enrolled in BiB in the United Kingdom. This suggests that etiology of the disease differs between ethnic groups and that ethnic-appropriate prevention strategies may be beneficial.

Interplay between demographic, clinical and polygenic risk factors for severe COVID-19.

BACKGROUND: We aimed to identify clinical, socio-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) in the general population. METHODS: In this observational study, we identified 9560 UK Biobank participants diagnosed with COVID-19 during 2020. A polygenic risk score (PRS) for severe COVID-19 was derived and optimized using publicly available European and trans-ethnic COVID-19 genome-wide summary statistics. We estimated the risk of hospital or critical care admission within 28 days or death within 100 days following COVID-19 diagnosis, and assessed associations with socio-demographic factors, immunosuppressant use and morbidities reported at UK Biobank enrolment (2006-2010) and the PRS. To improve biological understanding, pathway analysis was performed using genetic variants comprising the PRS. RESULTS: We included 9560 patients followed for a median of 61 (interquartile range = 34-88) days since COVID-19 diagnosis. The risk of severe COVID-19 increased with age and obesity, and was higher in men, current smokers, those living in socio-economically deprived areas, those with historic immunosuppressant use and individuals with morbidities and higher co-morbidity count. An optimized PRS, enriched for single-nucleotide polymorphisms in multiple immune-related pathways, including the 'oligoadenylate synthetase antiviral response' and 'interleukin-10 signalling' pathways, was associated with severe COVID-19 (adjusted odds ratio 1.32, 95% CI 1.11-1.58 for the highest compared with the lowest PRS quintile). CONCLUSION: This study conducted in the pre-SARS-CoV-2-vaccination era, emphasizes the novel insights to be gained from using genetic data alongside commonly considered clinical and socio-demographic factors to develop greater biological understanding of severe COVID-19 outcomes.

Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1.

The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.

Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts.

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.

Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma.

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 (P < 0.05/74, 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.

Ethnic-specific associations between dietary consumption and gestational diabetes mellitus incidence: A meta-analysis.

Globally, one in seven pregnant women are diagnosed with gestational diabetes mellitus (GDM), conferring short- and long-term health risks to both mother and child. While dietary prevention strategies are common in clinical practice, their effectiveness in different ethnicities is uncertain. To better inform prevention strategies, here the effects of unhealthy and healthy diets on GDM risk within distinct ethnic or cultural populations and geographic regions were evaluated and summarised. Pubmed, Scopus, Cochrane and OVID were systematically searched to identify randomised controlled trials (RCTs) and observational studies that investigated diet and GDM. A grouped analysis of common 'healthy' and 'unhealthy' diets was performed first, before analysing individual dietary patterns (e.g., prudent, Mediterranean). Random effect models and dose response analyses were performed where possible. PROSPERO (CRD42019140873). Thirty-eight publications provided information on 5 population groups: white European (WE), Asian, Iranian, Mediterranean and Australian. No associations were identified between healthy diets and GDM incidence in RCTs in any population. However, when synthesizing observational studies, healthy diets reduced odds of GDM by 23% (95% CI: 0.70-0.89, p<0.001, I2 = 75%), while unhealthy diets increased odds of GDM by 61% (95% CI: 1.41-1.81, p<0.0001, I2 = 0%) in WE women. No evidence of consistent effects in other populations were observed, even when adequately powered. Diet consistently associated with GDM risk in WEs but not in other populations. Heterogenous use and reporting of ethnically and culturally appropriate diets and dietary assessment tools, particularly in RCTs, raises uncertainty regarding the lack of association found in non-WE populations. Future studies require the use of culturally appropriate tools to confidently evaluate dietary and metabolic mediators of GDM and inform culturally-specific dietary prevention strategies.

Fine-scale population structure and demographic history of British Pakistanis.

Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low recent effective population sizes (Ne), with some showing a decrease 15‒20 generations ago that has resulted in extensive identity-by-descent sharing and homozygosity, increasing the risk of recessive disorders. Our results from two orthogonal methods (one using machine learning and the other coalescent-based) suggest that the detailed reporting of parental relatedness for mothers in the cohort under-represents the true levels of consanguinity. These results demonstrate the impact of cultural practices on population structure and genomic diversity in Pakistanis, and have important implications for medical genetic studies.