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The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public–private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics 1 . The Pharma Proteomics Project generates the largest open-access plasma proteomics dataset to date, offering insights into trans protein quantitative trait loci across multiple biological domains, and highlighting genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks.

Host genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function in 7,738 participants of the Dutch Microbiome Project. Two robust, study-wide significant ( P  < 1.89 × 10 −10 ) signals near the LCT and ABO genes were found to be associated with multiple microbial taxa and pathways and were replicated in two independent cohorts. The LCT locus associations seemed modulated by lactose intake, whereas those at ABO could be explained by participant secretor status determined by their FUT2 genotype. Twenty-two other loci showed suggestive evidence ( P  < 5 × 10 −8 ) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci we identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome. A genome-wide association study of 207 taxa and 205 pathways representing gut microbial composition and function from 7,738 individuals of the Dutch Microbiome Project identifies genetic associations at the LCT and ABO loci.

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established 1 – 6 , little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N -acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO -associated species can also utilize GalNAc, particularly Collinsella aerofaciens . The GalNAc utilization genes are also associated with the host’s cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host–microbiome relationship. A meta-analysis of associations between human genetic variation and gut microbial structural variations shows that ABO genotype differentially affects the presence of Faecalibacterium prausnitzii strains containing GalNAc utilization pathway in the gut.

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2 – 4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling ( IL10RB and PLSCR1 ), leucocyte differentiation ( BCL11A ) and blood-type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase ( ATP11A ), and increased expression of a mucin ( MUC1 )—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules ( SELE , ICAM5 and CD209 ) and the coagulation factor F8 , all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease. Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

The human gut microbiome is a complex ecosystem that is involved in its host’s metabolism, immunity and health. Although interindividual variations in gut microbial composition are mainly driven by environmental factors, some gut microorganisms are heritable and thus can be influenced by host genetics. In the past 5 years, 12 microbial genome-wide association studies (mbGWAS) with >1,000 participants have been published, yet only a few genetic loci have been consistently confirmed across multiple studies. Here we discuss the state of the art for mbGWAS, focusing on current challenges such as the heterogeneity of microbiome measurements and power issues, and we elaborate on potential future directions for genetic analysis of the microbiome. This Perspective discusses the analytical issues concerning heterogeneity and power encountered in microbial genome-wide association studies and highlights potential future directions for genetic analysis of the microbiome.

Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1 , MUC6, FUT2 , PSCA , ABO , CDX2, GAST and CCKBR . There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder. Genetic factors contribute to peptic ulcer disease (PUD). Here, the authors perform a genome-wide association analysis on PUD in the UK Biobank, highlighting shared architecture with other gastrointestinal disorders and possible causal links with depression.

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory 1 , 2 , neurologic 3 and neoplastic diseases 4 . Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain 5 – 11 . Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition 11 . In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a ‘metaorganism’ broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management. Genome-wide association analysis of 8,956 German individuals identifies 38 genetic loci associated with single bacteria and overall microbiome composition.

Background and aims Previous study disclosed Fucosyltransferase 2 ( Fut2 ) gene as a IBD risk locus. This study aimed to explore the mechanism of Fut2 in IBD susceptibility and to propose a new strategy for the treatment of IBD. Methods Intestinal epithelium-specific Fut2 knockout ( Fut2 △IEC ) mice was used. Colitis was induced by dextran sulfate sodium (DSS). The composition and diversity of gut microbiota were assessed via 16S rRNA analysis and the metabolomic findings was obtained from mice feces via metabolite profiling. The fecal microbiota transplantation (FMT) experiment was performed to confirm the association of gut microbiota and LPC. WT mice were treated with Lysophosphatidylcholine (LPC) to verify its impact on colitis. Results The expression of Fut 2 and α-1,2-fucosylation in colonic tissues were decreased in patients with UC (UC vs. control, P  = 0.036) and CD (CD vs. control, P  = 0.031). When treated with DSS, in comparison to WT mice, more severe intestinal inflammation and destructive barrier functions in Fut2 △IEC mice was noted. Lower gut microbiota diversity was observed in Fut2 △IEC mice compared with WT mice ( p  < 0.001). When exposed to DSS, gut bacterial diversity and composition altered obviously in Fut2 △IEC mice and the fecal concentration of LPC was increased. FMT experiment revealed that mice received the fecal microbiota from Fut2 △IEC mice exhibited more severe colitis and higher fecal LPC concentration. Correlation analysis showed that the concentration of LPC was positively correlated with four bacteria— Escherichia , Bilophila , Enterorhabdus and Gordonibacter . Furthermore, LPC was proved to promote the release of pro-inflammatory cytokines and damage epithelial barrier in vitro and in vivo . Conclusion Fut 2 and α-1,2-fucosylation in colon were decreased not only in CD but also in UC patients. Gut microbiota in Fut2 △IEC mice is altered structurally and functionally, promoting generation of LPC which was proved to promote inflammation and damage epithelial barrier.

Noroviruses are the most common etiological agent of acute gastroenteritis worldwide. Despite their high infectivity, a subpopulation of individuals is resistant to infection and disease. This susceptibility is norovirus genotype-dependent and is largely mediated by the presence or absence of human histo-blood group antigens (HBGAs) on gut epithelial surfaces. The synthesis of these HBGAs is mediated by fucosyl- and glycosyltransferases under the genetic control of the FUT2 (secretor), FUT3 (Lewis) and ABO(H) genes. The so-called non-secretors, having an inactivated FUT2 enzyme, do not express blood group antigens and are resistant to several norovirus genotypes, including the predominant GII.4. Significant genotypic and phenotypic diversity of HBGA expression exists between different human populations. Here, we review previous in vivo studies on genetic susceptibility to norovirus infection. These are discussed in relation to population susceptibility, vaccines, norovirus epidemiology and the impact on public health.

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.