Polygenic risk score portability for common diseases across genetically diverse populations.

Background: Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest.

Methods: To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet).

Neural ADMIXTURE for rapid genomic clustering.

Characterizing the genetic structure of large cohorts has become increasingly important as genetic studies extend to massive, increasingly diverse biobanks. Popular methods decompose individual genomes into fractional cluster assignments with each cluster representing a vector of DNA variant frequencies. However, with rapidly increasing biobank sizes, these methods have become computationally intractable.

The genomic history of the indigenous people of the Canary Islands.

The indigenous population of the Canary Islands, which colonized the archipelago around the 3 century CE, provides both a window into the past of North Africa and a unique model to explore the effects of insularity. We generate genome-wide data from 40 individuals from the seven islands, dated between the 3-16 centuries CE. Along with components already present in Moroccan Neolithic populations, the Canarian natives show signatures related to Bronze Age expansions in Eurasia and trans-Saharan migrations.

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease.

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.

Session Introduction: Overcoming health disparities in precision medicine.

The following sections are included: Overview, Equitable risk prediction, Pharmacoequity, Race, genetic ancestry, and population structure, Conclusion, Acknowledgments, References.

Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research.

Introduction: A major challenge to enabling precision health at a global scale is the bias between those who enroll in state sponsored genomic research and those suffering from chronic disease. More than 30 million people have been genotyped by direct-to-consumer (DTC) companies such as 23andMe, Ancestry DNA, and MyHeritage, providing a potential mechanism for democratizing access to medical interventions and thus catalyzing improvements in patient outcomes as the cost of data acquisition drops. However, much of these data are sequestered in the initial provider network, without the ability for the scientific community to either access or validate.

Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy.

The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California.

Ancient DNA reveals five streams of migration into Micronesia and matrilocality in early Pacific seafarers.

Micronesia began to be peopled earlier than other parts of Remote Oceania, but the origins of its inhabitants remain unclear. We generated genome-wide data from 164 ancient and 112 modern individuals. Analysis reveals five migratory streams into Micronesia.

Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes.

Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

Background: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking.

Results: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines.

Bayesian model comparison for rare-variant association studies.

Whole-genome sequencing studies applied to large populations or biobanks with extensive phenotyping raise new analytic challenges. The need to consider many variants at a locus or group of genes simultaneously and the potential to study many correlated phenotypes with shared genetic architecture provide opportunities for discovery not addressed by the traditional one variant, one phenotype association study. Here, we introduce a Bayesian model comparison approach called MRP (multiple rare variants and phenotypes) for rare-variant association studies that considers correlation, scale, and direction of genetic effects across a group of genetic variants, phenotypes, and studies, requiring only summary statistic data.

Paths and timings of the peopling of Polynesia inferred from genomic networks.

Polynesia was settled in a series of extraordinary voyages across an ocean spanning one third of the Earth, but the sequences of islands settled remain unknown and their timings disputed. Currently, several centuries separate the dates suggested by different archaeological surveys. Here, using genome-wide data from merely 430 modern individuals from 21 key Pacific island populations and novel ancestry-specific computational analyses, we unravel the detailed genetic history of this vast, dispersed island network.

Dynamic RNA Regulation in the Brain Underlies Physiological Plasticity in a Hibernating Mammal.

Hibernation is a physiological and behavioral phenotype that minimizes energy expenditure. Hibernators cycle between profound depression and rapid hyperactivation of multiple physiological processes, challenging our concept of mammalian homeostasis. How the hibernator orchestrates and survives these extremes while maintaining cell to organismal viability is unknown.

Discovering prescription patterns in pediatric acute-onset neuropsychiatric syndrome patients.

Objective: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a complex neuropsychiatric syndrome characterized by an abrupt onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two concomitant debilitating cognitive, behavioral, or neurological symptoms. A wide range of pharmacological interventions along with behavioral and environmental modifications, and psychotherapies have been adopted to treat symptoms and underlying etiologies. Our goal was to develop a data-driven approach to identify treatment patterns in this cohort.

Native American gene flow into Polynesia predating Easter Island settlement.

The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas, while critics have argued that these botanical dispersals need not have been human mediated. The Norwegian explorer Thor Heyerdahl controversially suggested that prehistoric South American populations had an important role in the settlement of east Polynesia and particularly of Easter Island (Rapa Nui).

FasTag: Automatic text classification of unstructured medical narratives.

Unstructured clinical narratives are continuously being recorded as part of delivery of care in electronic health records, and dedicated tagging staff spend considerable effort manually assigning clinical codes for billing purposes. Despite these efforts, however, label availability and accuracy are both suboptimal. In this retrospective study, we aimed to automate the assignment of top-level International Classification of Diseases version 9 (ICD-9) codes to clinical records from human and veterinary data stores using minimal manual labor and feature curation.

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used.

Development of a small panel of SNPs to infer ancestry in Chileans that distinguishes Aymara and Mapuche components.

Background: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African.

Genetic variation drives seasonal onset of hibernation in the 13-lined ground squirrel.

Hibernation in sciurid rodents is a dynamic phenotype timed by a circannual clock. When housed in an animal facility, 13-lined ground squirrels exhibit variation in seasonal onset of hibernation, which is not explained by environmental or biological factors. We hypothesized that genetic factors instead drive variation in timing.

Population History and Gene Divergence in Native Mexicans Inferred from 76 Human Exomes.

Native American genetic variation remains underrepresented in most catalogs of human genome sequencing data. Previous genotyping efforts have revealed that Mexico's Indigenous population is highly differentiated and substructured, thus potentially harboring higher proportions of private genetic variants of functional and biomedical relevance. Here we have targeted the coding fraction of the genome and characterized its full site frequency spectrum by sequencing 76 exomes from five Indigenous populations across Mexico.