Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2–2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10−8) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10−13), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1, MHC, DPP9 and IFNAR2). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone.

African Americans (AAs) are disproportionately affected by metabolic diseases and adverse drug events, with limited publicly available genomic and transcriptomic data to advance the knowledge of the molecular underpinnings or genetic associations to these diseases or drug response phenotypes. To fill this gap, we obtained 60 primary hepatocyte cultures from AA liver donors for genome-wide mapping of expression quantitative trait loci (eQTL) using LAMatrix. We identified 277 eGenes and 19,770 eQTLs, of which 67 eGenes and 7,415 eQTLs are not observed in the Genotype-Tissue Expression Project (GTEx) liver eQTL analysis. Of the eGenes found in GTEx only 25 share the same lead eQTL. These AA-specific eQTLs are less correlated to GTEx eQTLs. in effect sizes and have larger Fst values compared to eQTLs found in both cohorts (overlapping eQTLs). We assessed the overlap between GWAS variants and their tagging variants with AA hepatocyte eQTLs and demonstrated that AA hepatocyte eQTLs can decrease the number of potential causal variants at GWAS loci. Additionally, we identified 75,002 exon QTLs of which 48.8% are not eQTLs in AA hepatocytes. Our analysis provides the first comprehensive characterization of AA hepatocyte eQTLs and highlights the unique discoveries that are made possible due to the increased genetic diversity within the African ancestry genome.

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Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 379,066 exome-sequenced participants in the UK Biobank. We identified associations for variants in GCK, HNF1A and PDX1, which are known to be involved in Mendelian forms of diabetes. Notably, we uncovered novel associations for GIGYF1, a gene not previously implicated by human genetics in diabetes. GIGYF1 predicted loss of function (pLOF) variants associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 × 10–12) and HbA1c (4.33 mmol/mol, p = 1.28 × 10–14) as well as T2D diagnosis (OR = 4.15, p = 6.14 × 10–11). Multiple rare variants contributed to these associations, including singleton variants. GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. The association of GIGYF1 pLOF with T2D diagnosis replicated in an independent cohort from the Geisinger Health System. In addition, a common variant association for glucose and T2D was identified at the GIGYF1 locus. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.

Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explaining a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome‐wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly participants of European and Asian descent, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, describe the role of genetic variation in pharmacologic pathways, and highlight a number of population‐specific findings.

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IMPORTANCE Major warfarin-related bleeding occurs more frequently in African Americans than in other populations. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVE To identify genetic factors associated with warfarin-related bleeding in patients of African descent at an international normalized ratio (INR) of less than 4. DESIGN, SETTING, AND PARTICIPANTS A case-control genome-wide association study involving patients of African descent taking warfarin was conducted in a discovery cohort (University of Chicago [2009-2011] and the University of Illinois at Chicago [2002-2011]), and associations were confirmed in a replication cohort (University of Chicago [2015-2016]). Potential population stratification was examined in the discovery cohort by principal component analysis. Odds ratios (ORs) and 95% CIs were computed for bleeding risk by logistic regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis. The potential influence of single-nucleotide polymorphisms (SNPs) on gene expression was studied by luciferase expression assays. EXPOSURES Single-nucleotide polymorphisms associated with warfarin-related bleeding. MAIN OUTCOMES AND MEASURES Major bleeding-defined as bleeding requiring hospitalization, causing a decrease in hemoglobin level of more than 2 g/dL, requiring blood transfusion, or any combination of the 3-while taking warfarin at an INR of less than 4. RESULTS The discovery cohort consisted of 31 cases (mean age, 60.1 years [SD, 14.9 years], 26 women [83.9%]) and 184 warfarin-treated controls (mean age, 57.1 years [SD, 15.7 years]) with no documented bleeding. The replication cohort consisted of 40 cases (mean age, 55.6 years [SD, 17.3 years], 27 women [67.5%]), and 148 warfarin-treated controls (mean age, 55.4 years [SD, 17.1 years]; 98 women [66.2%]) with no documented bleeding. In the discovery cohort, 4 SNPs in linkage disequilibrium on chromosome 6 (rs115112393, rs16871327, rs78132896, and rs114504854) were associated with warfarin-related bleeding but did not reach genome-wide significance. The SNP rs78132896 occurred in 11 cases (35.5%) and 9 controls (4.9%) in the discovery cohort (OR, 8.31; 95% CI, 3.2-21.5; P < 6.21 × 10 −8), and the association was confirmed in the replication cohort (the SNP was present in 14 cases [35.0%] and 7 controls [4.8%]; OR, 8.24; 95% CI, 3.1-25.3, P = 5.64 × 10 −5). Genome-wide significance of this SNP was achieved when the cohorts were combined via meta-analysis (OR, 8.27; 95% CI, 4.18-16.38; P = 2.05 × 10 −11). These SNPs are found only in people of African descent. In vitro luciferase expression assays demonstrated that rs16871327 (enhancer SNP) and rs78132896 (promoter SNP) risk alleles together increased EPHA7 gene (Entrez Gene 2045) transcription by a mean of 14.95 (SD, 1.7) compared with wild-type alleles (mean, 9.56 [SD, 0.84]; difference, 5.39; 95% CI, 4.1-6.6; P < .001). CONCLUSIONS AND RELEVANCE In this prelim...