Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10−22 and p = 8.1x10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10−8) and ARHGAP33 (p = 1.3x10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

The variation in the allelic frequencies of polymorphic pharmacogenes among different ethnic groups may be responsible for severe adverse reactions to or altered efficacy of a wide variety of drugs. Amazonian Amerindian populations have a unique genetic profile that may have a fundamental on the efficacy and safety of certain drugs. The genetic characteristics of these populations are poorly known, which can negatively impact the systematic application of treatments guided by pharmacogenomic guidelines. We investigated the diversity of 32 polymorphisms in genes responsible for drug Absorption, Distribution, Metabolism and Excretion (ADME) in Amazonian Amerindians, and compared the findings with populations from other continents available in the 1000 Genomes database. We found significantly different ( P ≤ 1.56E-03) allelic frequencies and genotype distributions in many study markers in comparison with African, European, American and Asian populations. Based on FST values, the Amerindian population was also the most distinct (mean FST = 0.09917). These data highlight the unique genetic profile of the indigenous population from the Brazilian Amazon region, which is potentially important from a pharmacogenetic viewpoint. Understanding the diversity of ADME- related genetic markers is crucial to the implementation of individualized pharmacogenomic treatment protocols in Amerindian populations, as well as populations with a high degree of admixture with this ethnic group, such as the general Brazilian population.

AIMTo evaluate the relation between 12 polymorphisms and the development of gastric cancer (GC) and colorectal cancer (CRC).METHODSIn this study, we included 125 individuals with GC diagnosis, 66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms (in CASP8, CYP2E1, CYP19A1, IL1A, IL4, MDM2, NFKB1, PAR1, TP53, TYMS, UGT1A1 and XRCC1 genes) were genotyped in a single PCR for each individual, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 ancestry-informative markers that can also be genotyped by multiplex PCR. The statistical analyses were performed in Structure v.2.3.4, R environment and SPSS v.20.RESULTSAfter statistical analyses with the control of confounding factors, such as genetic ancestry, three markers (rs79071878 in IL4, rs3730485 in MDM2 and rs28362491 in NFKB1) were positively associated with the development of GC. One of these markers (rs28362491) and the marker in the UGT1A1 gene (rs8175347) were positively associated with the development of CRC. Therefore, we investigated whether the joint presence of the deleterious alleles of each marker could affect the development of cancer and we obtained positive results in all analyses. Carriers of the combination of alleles RP1 + DEL (rs79071878 and rs28361491, respectively) are at 10-times greater risk of developing GC than carriers of other combinations. Similarly, carriers of the combination of DEL + RARE (rs283628 and rs8175347) are at about 12-times greater risk of developing CRC than carriers of other combinations.CONCLUSIONThese findings are important for the comprehension of gastric and CRC development, particularly in highly admixed populations, such as the Brazilian population.

Acute lymphoblastic leukemia (ALL) is a malignant tumor common in children. Studies of genetic susceptibility to cancer using biallelic insertion/deletion (INDEL) type polymorphisms associated with cancer development pathways may help to clarify etymology of ALL. In this study, we investigate the role of eight functional INDEL polymorphisms and influence of genetic ancestry to B-cell ALL susceptibility in children of Brazilian Amazon population, which has a high degree of inter-ethnic admixture. Ancestry analysis was estimated using a panel of 48 autosomal ancestry informative markers. 130 B-cell ALL patients and 125 healthy controls were included in this study. The odds ratios and 95% confidence intervals were adjusted for confounders. The results indicated an association between the investigated INDEL polymorphisms in CASP8 (rs3834129), CYP19A1 (rs11575899) e XRCC1 (rs3213239) genes in the development of B-cell ALL. The carriers of Insertion/Insertion (Ins/Ins) genotype of the polymorphism in CASP8 gene presented reduced chances of developing B-cell ALL (P=0.001; OR=0.353; 95% CI=0.192-0.651). The Deletion/Deletion (Del/Del) genotype of the polymorphism in CYP19A1 gene was associated to a lower chance of developing B-cell ALL (P=3.35×10; OR=0.121; 95% CI=0.050-0.295), while Del/Del genotype of the polymorphism in XRCC1 gene was associated to a higher chance of developing B-cell ALL (P=2.01×10; OR=6.559; 95% CI=2.433-17.681). We also found that Amerindian ancestry correlates with the risk of B-cell ALL. For each increase of 10% in the Amerindian ancestry results in 1.4-fold chances of developing B-cell ALL (OR=1.406; 95% IC=1.123-1.761), while each increase of 10% in the European ancestry presents a protection effect in the development of B-cell ALL (OR=0.666; 95% IC=0.536-0.827). The results suggest that genetic factors influence leukemogenesis and might be explored in the stratification of B-cell ALL risk in admixed populations.