Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

Human pigmentation has largely been associated with different disease prevalence among populations, but most of these studies are observational and inconclusive. Known to be genetically determined, pigmentary traits have largely been studied by Genome-Wide Association Study (GWAS), mostly in Caucasian ancestry cohorts from North Europe, identifying robustly, several loci involved in many of the pigmentary traits. Here, we conduct a detailed analysis by GWAS and Polygenic Risk Score (PRS) of 13 pigmentary-related traits in a South European cohort of Caucasian ancestry (n = 20,000). We observed fair phototype strongly associated with non-melanoma skin cancer and other dermatoses and confirmed by PRS-approach the shared genetic basis with skin and eye diseases, such as melanoma (OR = 0.95), non-melanoma skin cancer (OR = 0.93), basal cell carcinoma (OR = 0.97) and darker phototype with vitiligo (OR = 1.02), cataracts (OR = 1.04). Detailed genetic analyses revealed 37 risk loci associated with 10 out of 13 analyzed traits, and 16 genes significantly associated with at least two pigmentary traits. Some of them have been widely reported, such as MC1R, HERC2, OCA2, TYR, TYRP1, SLC45A2, and some novel candidate genes C1QTNF3, LINC02876, and C1QTNF3-AMACR have not been reported in the GWAS Catalog, with regulatory potential. These results highlight the importance of the assess phototype as a genetic proxy of skin functionality and disease when evaluating open mixed populations.

We investigated the association between outdoor artificial light-at-night (ALAN) exposure and cardiometabolic risk in the GCAT study. We included 9752 participants from Barcelona (59% women) and used satellite images (30 m resolution) and estimated photopic illuminance and the circadian regulation–relevant melanopic equivalent daylight illuminance (melanopic EDI). We explored the association between ALAN exposure and prevalent obesity, hypertension, and diabetes with logistic regressions and assessed the relationship with incident cardiometabolic diseases ascertained through electronic health records (mean follow-up 6.5 years) with Cox proportional hazards regressions. We observed an association between photopic illuminance and melanopic EDI and prevalent hypertension, odds ratio (OR) = 1.09 (95% CI, 1.01-1.16) and 1.08 (1.01-1.14) per interquartile range increase (0.59 and 0.16 lux, respectively). Both ALAN indicators were linked to incident obesity (hazard ratio [HR] = 1.29, 1.11-1.48 and 1.19, 1.05-1.34) and hemorrhagic stroke (HR = 1.73, 1.00-3.02 and 1.51, 0.99-2.29). Photopic illuminance was associated with incident hypercholesterolemia in all participants (HR = 1.17, 1.05-1.31) and with angina pectoris only in women (HR = 1.55, 1.03-2.33). Further research in this area and increased awareness on the health impacts of light pollution are needed. Results should be interpreted carefully since satellite-based ALAN data do not estimate total individual exposure. This article is part of a Special Collection on Environmental Epidemiology.

Population-based cohorts play a key role in personalized medicine. However, it is known that cohorts are affected by the “healthy volunteer bias” where participants are generally healthier than the broader population, compromising its representativeness. Here, we assess the healthy bias, identifying bias key indicators for representativeness of the GCAT cohort, encompassing 20,000 adult participants of Catalonia, and generating survey raked weights to enhance the cohort’s comparability. To assess and correct the bias, we compare multiple variables across sociodemographic, lifestyle, diseases and medication domains. Electronic health records of Catalonia (SIDIAP), the Health Survey of Catalonia (ESCA) and registers from the statistics institute of Catalonia (IDESCAT) and Spain (INE) were used to make the comparisons. We observed that the GCAT cohort is enriched in women and younger individuals, people with higher socioeconomic status and more health conscious and healthier individuals in terms of mortality and chronic disease prevalence. Raked survey weighting identified sex, birth year, rurality, education level, civil status, occupation status, smoking habit, household size, self-perceived health status and number of primary care visits as key weight variables. On average, raked weights reduced the differences by 70% for compared variables, and by 26% in disease prevalence estimates. We can conclude that the application of raked weights has enhanced the cohort’s representativeness, improved comparability, and yielded more precise estimates when analysing GCAT data.

BACKGROUND: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking. METHODS: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data. RESULTS: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P =4.34×10 ⁻⁸ ). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings. CONCLUSIONS: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Blood transfusions, conducted between donors compatible in their red blood cell (RBC) antigens, play a life-saving role in transfusion medicine. Genetic differences at blood group loci between ethnicities result in diversity and altered frequency of RBC antigens that need to be considered in blood transfusion. Consequently, comprehensive, and accurate blood group antigen typing is especially relevant for inter-ethnic blood transfusions and for minorities underrepresented in the donor population. Blood group microarray genotyping is a cost-efficient and scalable method for comprehensive blood group typing. Previously, however, microarray typing has been challenging for the clinically important blood group systems Rh and MNS, as these feature highly paralogous genomic loci leading to mixed signals. We here present an approach for accurately typing blood group systems, including Rh and MNS variations, that we benchmarked in an ethnically diverse cohort. We tested its performance using gold-standard, diagnostic-grade MALDI-TOF data from 1,052-samples, including 334 CEPH diversity samples and applied the approach to 4,999 samples of a COVID-19 genetics study. Overall, we obtained a 99.95% benchmarking concordance and 99.65% call rate. In summary, we provide a highly accurate and cost-efficient high-throughput genotyping method for comprehensive blood group analysis that is also suitable for ethnically diverse sample sets.