BACKGROUNDThere is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 . Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODSWe conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTSWe detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10 −8 ) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10 −10 ; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10 −8 , respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10 −4 ) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10 −5 ). CONCLUSIONSWe identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.

SummaryOverweight and obesity affect ~1.5 billion people worldwide, and are major risk factors for type-2 diabetes (T2D), cardiovascular disease and related metabolic and inflammatory disturbances.1,2 Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation,3–6 a key regulator of gene expression and molecular phenotype.7 Here we use epigenome-wide association to show that body mass index (BMI, a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci at P<1x10-7, range P=9.2x10-8 to 6.0x10-46; N=10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find the methylation loci are enriched for functional genomic features in multiple tissues (P<0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P<9.0x10-6, range P=5.5x10-6 to 6.1x10-35, N=1,785 samples). The methylation loci identified highlight genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future type-2 diabetes (relative risk per 1SD increase in Methylation Risk Score: 2.3 [2.07-2.56]; P=1.1x10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type-2 diabetes and other adverse clinical consequences of obesity.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5m genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N≤71,225 European ancestry, N=12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N=29,136). We identified association between systolic or diastolic blood pressure and common variants in 8 regions near the CYP17A1 (P=7×10−24), CYP1A2 (P=1×10−23), FGF5 (P=1×10−21), SH2B3 (P=3×10−18), MTHFR (P=2×10−13), c10orf107 (P=1×10−9), ZNF652 (P=5×10−9) and PLCD3 (P=1×10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

The common sequence variants that have recently been associated with cancer risk are particular to a single, or at most two, cancer types. Following up on our genome-wide scan of basal cell carcinoma1, we identified rs401681(C) on chromosome 5p15.33 satisfying our threshold for genome-wide significance (OR=1.25, P=3.7×10−12). We tested rs401681 for association with sixteen additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR=1.15, P=7.2×10−8) and urinary bladder, prostate and cervix cancer (ORs 1.07–1.31, all P<4×10−4). However, rs401681(C) appears to confer protection against cutaneous melanoma (OR=0.88, P=8.0×10−4). Interestingly, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098(A), that showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. Rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein while rs401681 is in an intron of the CLPTM1L gene.