A second update on mapping the human genetic architecture of COVID-19

Matters Arising From: COVID-19 Host Genetics Initiative. Nature https://doi.org/10.1038/s41586-021-03767-x (2021)Data availability: Summary statistics generated by the COVID-19 HGI are available online, including per-ancestry summary statistics for African, admixed American, East Asian, European and South Asian ancestries (https://www.covid19hg.org/results/r7/). The analyses described here used the data release 7. If available, individual-level data can be requested directly from contributing studies, listed in Supplementary Table 1. We used publicly available data from GTEx (https://gtexportal.org/home/), the Neale laboratory (http://www.nealelab.is/uk-biobank/), the Finucane laboratory (https://www.finucanelab.org), the FinnGen Freeze 4 cohort (https://www.finngen.fi/en/access_results) and the eQTL catalogue release 3 (http://www.ebi.ac.uk/eqtl/).Code availability: The code for summary statistics lift-over, the projection PCA pipeline including precomputed loadings and meta-analyses (https://github.com/covid19-hg/); for heritability estimation (https://github.com/AndrewsLabUCSF/COVID19_heritability); for Mendelian randomization and genetic correlation (https://github.com/marcoralab/MRcovid); and subtype analyses (https://github.com/mjpirinen/covid19-hgi_subtypes) are available at GitHub.Reporting summary: Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article online at: https://www.nature.com/articles/s41586-023-06355-3#MOESM2 .Supplementary information is available online at: https://www.nature.com/articles/s41586-023-06355-3#Sec4 .Copyright © The Author(s) 2023. Investigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development1,2. Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release2. The increased number of candidate genes at the identified loci helped to map three major biological pathways that are involved in susceptibility and severity: viral entry, airway defence in mucus and type I interferon

High-depth African genomes inform human migration and health

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals—comprising 50 ethnolinguistic groups, including previously unsampled populations—to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon—but in other genes, variants denoted as ‘likely pathogenic’ in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.Radiolog

High-depth African genomes inform human migration and health

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals—comprising 50 ethnolinguistic groups, including previously unsampled populations—to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon—but in other genes, variants denoted as ‘likely pathogenic’ in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health

What works in engaging communities?: prioritising nutrition interventions in Burkina Faso, Ghana and South Africa

Background: "Choosing All Together" (CHAT), is a community engagement tool designed to give the public a voice in how best to allocate limited resources to improve population health. This process evaluation explored the mechanisms through which CHAT generates community engagement.Method: the CHAT tool was adapted and implemented for use in two rural communities (Nanoro, Burkina Faso, and Navrongo, Ghana) and one urban township (Soweto, South Africa) to prioritize maternal and child nutrition interventions. Community discussions were audio-recorded, transcribed, and translated into English. Twenty-two transcripts, including six each from Navrongo and Soweto and 10 from Nanoro, were analysed thematically to generate data driven codes and themes to explain mechanisms underlying the CHAT process. The process evaluation was based on the UK MRC process evaluation guidance.Results: seven themes describing the functions and outcomes of CHAT were identified. Themes described participants deliberating trade-offs, working together, agreeing on priorities, having a shared vision, and increasing their knowledge, also the skills of the facilitator, and a process of power sharing between participants and researchers. Participants came to an agreement of priorities when they had a shared vision. Trained facilitators are important to facilitate meaningful discussion between participants and those with lower levels of literacy to participate fully.Conclusion: CHAT has been shown to be adaptable and useful in prioritising maternal and child nutrition interventions in communities in Burkina Faso, Ghana, and South Africa. Conducting CHAT in communities over a longer period and involving policy-makers would increase trust, mutual respect and develop partnerships.</p

Men’s motivations, barriers to and aspirations for their families’ health in the first 1000 days in sub-Saharan Africa: a secondary qualitative analysis

Introduction The first 1000 days of life are a critical period of growth and development that have lasting implications for health, cognitive, educational and economic outcomes. In sub-Saharan Africa, gender and social norms are such that many men have little engagement with maternal and child health and nutrition during pregnancy and early childhood. This study explores how men perceive their role in three sites in sub-Saharan Africa.Methods Secondary qualitative analysis of 10 focus group discussions with 76 men in Burkina Faso, Ghana and South Africa. Data were thematically analysed to explore men’s perceptions of maternal and child health and nutrition.Results Men considered themselves ‘providers’ and 'advisors' within their families, particularly of finances, food and medicines. They also indicated that this advice was out of care and concern for their families’ health. There were similarities in how the men perceive their role. Differences between men living in rural and urban settings included health priorities, the advice and the manner in which it was provided. Across all settings, men wanted to be more involved with maternal and child health and nutrition. Challenges to doing so included stigma and proscribed social gender roles.Conclusion Men want a greater engagement in improving maternal and child health and nutrition but felt that their ability to do so was limited by culture-specified gender roles, which are more focused on providing for and advising their families. Involving both men and women in intervention development alongside policymakers, health professionals and researchers is needed to improve maternal and child health and nutrition

Somatostatin sst(5) inhibition of receptor mediated regeneration of rat aortic vascular smooth muscle cells

1. The aim of the present study was to determine the effect of somatostatin (SRIF) on mitogen-induced regeneration of rat aortic vascular smooth muscle cells (VSMC) and for comparison Chinese hamster ovary (CHO)-K1 cells expressing human recombinant sst(5) receptors (CHOsst(5)), following partial denudation of a confluent cell monolayer. Regeneration was assessed by measuring areas of recovery into the denuded area and by counting total cell numbers. 2. In VSMC, SRIF (0.1 nM–1 μM) had no effect on the basal levels of regeneration but caused a concentration-dependent inhibition (pIC(50) 8.0–8.6) of the stimulated regeneration induced by sub-maximal concentrations of basic fibroblast growth factor (bFGF, 10 ng ml(−1)), platelet-derived growth factor-BB (PDGF, 5 ng ml(−1)) or endothelin-1 (ET-1, 100 nM). SRIF (pIC(50) 8.8) also inhibited bFGF-induced regeneration of CHOsst(5) cells. 3. In VSMC, the inhibitory action of SRIF on the regeneration induced by bFGF (10 ng ml(−1)) was due to an anti-proliferative effect, rather than an effect on cell migration, as SRIF (0.1 nM–1 μM) abolished bFGF-induced increases in total cell numbers. The bFGF-induced increase in cell numbers was also abolished by actinomycin D (0.1 μg ml(−1)). 4. The sst(5) receptor-selective agonist, L-362,855 (pIC(50) 10.5), was about 100 times more potent than SRIF at inhibiting bFGF-induced regeneration of both VSMC and CHOsst(5) cells whilst the sst(2) receptor-selective agonist, BIM-23027 (pIC(50) 6.8), was approximately 20 times weaker than SRIF. 5. The sst(5) receptor antagonist, BIM-23056 (100 nM), antagonized SRIF-induced inhibition of bFGF-induced regeneration in both VSMC and CHOsst(5) cells (estimated pK(B) values 8.8 and 8.3, respectively). 6. SRIF-induced inhibition of bFGF-induced regeneration of VSMC and CHOsst(5) cells was abolished by pretreating cells with pertussis toxin (100 ng ml(−1)) for 20 h. 7. These findings suggest that SRIF-induced inhibition of the proliferation of rat aortic VSMC is mediated via activation of receptors which are similar to human sst(5) receptors. Furthermore this inhibitory effect is transduced via pertussis toxin-sensitive G(i)/G(o) proteins

Global epidemiology of yaws: a systematic review

BACKGROUND: To achieve yaws eradication, the use of the new WHO strategy of initial mass treatment with azithromycin and surveillance twice a year needs to be extended everywhere the disease occurs. However, the geographic scope of the disease is unknown. We aimed to synthesise published and unpublished work to update the reported number of people with yaws at national and subnational levels and to estimate at-risk populations. METHODS: We searched PubMed and WHO databases to identify published data for prevalence of active and latent yaws from Jan 1, 1990, to Dec 31, 2014. We also searched for ongoing or recently completed unpublished studies from the WHO yaws surveillance network. We estimated yaws prevalence (and 95% CIs). We collected yaws incidence data from official national surveillance programmes at the first administrative level from Jan 1, 2010, to Dec 31, 2013, and we used total population data at the second administrative level to estimate the size of at-risk populations. FINDINGS: We identified 103 records, of which 23 published articles describing 27 studies and four unpublished studies met the inclusion criteria. Prevalence of active disease ranged from 0.31% to 14.54% in yaws-endemic areas, and prevalence of latent yaws ranged from 2.45% to 31.05%. During 2010-13, 256 343 yaws cases were reported to WHO from 13 endemic countries, all of which are low-income and middle-income countries. 215 308 (84%) of 256 343 cases reported to WHO were from three countries-Papua New Guinea, Solomon Islands, and Ghana. We estimated that, in 2012, over 89 million people were living in yaws-endemic districts. INTERPRETATION: Papua New Guinea, Solomon Islands, and Ghana should be the focus of initial efforts at implementing the WHO yaws eradication strategy. Community-based mapping and active surveillance must accompany the implementation of yaws eradication activities. FUNDING: None