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Polygenic risk scores (PRSs) aggregate the many small effects of alleles across the human genome to estimate the risk of a disease or disease-related trait for an individual. The potential benefits of PRSs include cost-effective enhancement of primary disease prevention, more refined diagnoses and improved precision when prescribing medicines. However, these must be weighed against the potential risks, such as uncertainties and biases in PRS performance, as well as potential misunderstanding and misuse of these within medical practice and in wider society. By addressing key issues including gaps in best practices, risk communication and regulatory frameworks, PRSs can be used responsibly to improve human health. Here, the International Common Disease Alliance's PRS Task Force, a multidisciplinary group comprising expertise in genetics, law, ethics, behavioral science and more, highlights recent research to provide a comprehensive summary of the state of polygenic score research, as well as the needs and challenges as PRSs move closer to widespread use in the clinic. As polygenic risk scores move closer to widespread clinical use, this Perspective summarizes the benefits, risks and challenges to be overcome., Author(s): Adebowale Adeyemo [sup.1] [sup.1] , Mary K. Balaconis [sup.2] , Deanna R. Darnes [sup.3] , Segun Fatumo [sup.4] [sup.5] [sup.6] , Palmira Granados Moreno [sup.7] , Chani J. Hodonsky [...]

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 surveyed.sup.1. 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. Whole-genome sequencing analyses of African populations provide insights into continental migration, gene flow and the response to human disease, highlighting the importance of including diverse populations in genomic analyses to understand human ancestry and improve health., Author(s): Ananyo Choudhury [sup.1] , Shaun Aron [sup.1] , Laura R. Botigué [sup.2] , Dhriti Sengupta [sup.1] , Gerrit Botha [sup.3] , Taoufik Bensellak [sup.4] , Gordon Wells [sup.5] [sup.6] [...]

Ferroptosis--an iron-dependent, non-apoptotic cell death process--is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers.sup.1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions.sup.2-5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis. The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions., Author(s): Yilong Zou [sup.1] [sup.2] , Whitney S. Henry [sup.3] , Emily L. Ricq [sup.1] [sup.2] , Emily T. Graham [sup.1] , Vaishnavi V. Phadnis [sup.3] , Pema Maretich [sup.4] [...]

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism.sup.1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases. A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes., Author(s): Deborah J. Thompson [sup.1] , Giulio Genovese [sup.2] [sup.3] [sup.4] , Jonatan Halvardson [sup.5] , Jacob C. Ulirsch [sup.3] [sup.6] , Daniel J. Wright [sup.7] [sup.8] , Chikashi Terao [...]

For a fortunate group, exercise and the right diet could protect against cognitive symptoms that develop with age. For a fortunate group, exercise and the right diet could protect against cognitive symptoms that develop with age, Author Affiliations: Physical activity could help to reduce the risk of dementia, at least in people without a strong genetic predisposition for the condition. [see PDF for image] Credit: Melanie [...]

Poly(ADP-ribose) polymerase (PARP) inhibition is emerging as a hot area of tumor therapy, and two recent clinical trials consolidate the potential of PARP inhibitors against two types of cancer. In [...]