117 research outputs found

    Hundreds of variants clustered in genomic loci and biological pathways affect human height

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    Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

    One Hundred Priority Questions for the Development of Sustainable Food Systems in Sub-Saharan Africa

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    Sub-Saharan Africa is facing an expected doubling of human population and tripling of food demand over the next quarter century, posing a range of severe environmental, political, and socio-economic challenges. In some cases, key Sustainable Development Goals (SDGs) are in direct conflict, raising difficult policy and funding decisions, particularly in relation to trade-offs between food production, social inequality, and ecosystem health. In this study, we used a horizon-scanning approach to identify 100 practical or research-focused questions that, if answered, would have the greatest positive impact on addressing these trade-offs and ensuring future productivity and resilience of food-production systems across sub-Saharan Africa. Through direct canvassing of opinions, we obtained 1339 questions from 331 experts based in 55 countries. We then used online voting and participatory workshops to produce a final list of 100 questions divided into 12 thematic sections spanning topics from gender inequality to technological adoption and climate change. Using data on the background of respondents, we show that perspectives and priorities can vary, but they are largely consistent across different professional and geographical contexts. We hope these questions provide a template for establishing new research directions and prioritising funding decisions in sub-Saharan Africa

    Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans

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    Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans

    Meta-analysis of genome-wide association studies of stable warfarin dose in patients of African ancestry.

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    Warfarin dose requirements are highly variable due to clinical and genetic factors. While genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWAS) in four African cohorts from Uganda, South Africa, and Zimbabwe, totalling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included two African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n=316) and the University of Alabama at Birmingham (n=199). Following the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci (the CYP2C cluster SNP rs12777823 and CYP2C9 in chromosome 10; VKORC1 in chromosome 16). The genome-wide significance threshold was set at PA revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P=3.64×10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, our meta-analysis of six cohorts of warfarin-treated patients of African ancestry reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements. We also identified a new locus (MALL), that still requires direct evidence of biological plausibility

    Genome-wide association analysis identifies six new loci associated with forced vital capacity

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    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR129-2–HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease

    Measuring the predictability of life outcomes with a scientific mass collaboration.

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    How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences

    Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

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    Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets
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