Facilitating return of actionable genetic research results from a biobank repository: Participant uptake and utilization of digital interventions.

Research participants report interest in receiving genetic research results. How best to return results remains unclear. In this randomized pilot study, we sought to assess the feasibility of returning actionable research results through a two-step process including a patient-centered digital intervention as compared with a genetic counselor (GC) in the Penn Medicine biobank.

Characterizing the pathogenicity of genetic variants: the consequences of context.

Beyond initial discovery of a pathogenic variant, establishing that a variant is recurrently associated with disease is important for understanding clinical impact and disease etiology. Disappointingly, our ability to characterize pathogenicity under varied circumstances is limited. Here we discuss the role of genetic and environmental background and how it affects variant penetrance and outcomes.

The Penn Medicine BioBank: Towards a Genomics-Enabled Learning Healthcare System to Accelerate Precision Medicine in a Diverse Population.

The Penn Medicine BioBank (PMBB) is an electronic health record (EHR)-linked biobank at the University of Pennsylvania (Penn Medicine). A large variety of health-related information, ranging from diagnosis codes to laboratory measurements, imaging data and lifestyle information, is integrated with genomic and biomarker data in the PMBB to facilitate discoveries and translational science. To date, 174,712 participants have been enrolled into the PMBB, including approximately 30% of participants of non-European ancestry, making it one of the most diverse medical biobanks.

Late-onset neonatal sepsis: genetic differences by sex and involvement of the NOTCH pathway.

Background: Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility.

Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood.

Jewish anatomic pathologists in the time of Italian Racial Laws.

The persecutions of the Jews that began with legislation introduced by Italy's fascist government in the year 1938 ("Leggi Razziali" i.e. "Racial Laws") also affected the sphere of anatomic pathology, coming to bear on Italian physicians belonging to the Jewish communities of several cities and universities.

Malaria protection due to sickle haemoglobin depends on parasite genotype.

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples.

Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection.

We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection ( , and ). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. At , we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function.

Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection.

We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (, , , and ). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. At , we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function.

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential.

A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.

Embracing African Genetic Diversity.

Williams, Sirugo, and Tishkoff discuss the recent article by Choudhury et al. reporting the whole-genome sequencing of 426 sub-Saharan African individuals and its contribution to the study of genetic diversity to understand human evolutionary history and health.

Methylome-wide Analysis Reveals Epigenetic Marks Associated With Resistance to Tuberculosis in Human Immunodeficiency Virus-Infected Individuals From East Africa.

Background: Tuberculosis (TB) is the most deadly infectious disease globally and is highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation.

CLEC4E (Mincle) genetic variation associates with pulmonary tuberculosis in Guinea-Bissau (West Africa).

Tuberculosis (TB) is the leading cause of death from a single infectious agent. According to the WHO, 85% of cases in 2018 were pulmonary tuberculosis (PTB), making it the most prevalent form of the disease. Although the bacillus responsible for disease, Mycobacterium tuberculosis (MTB), is estimated to infect 1.

Interferon-gamma polymorphisms and risk of iron deficiency and anaemia in Gambian children.

: Anaemia is a major public health concern especially in African children living in malaria-endemic regions. Interferon-gamma (IFN-γ) is elevated during malaria infection and is thought to influence erythropoiesis and iron status. Genetic variants in the IFN-γ gene ) are associated with increased IFN-γ production.