Co-first authors Drs. Kullo, Conomos, and Nelson will present an introduction and overview of the NIH-funded PRIMED Consortium, which is working to improve polygenic risk prediction of a range of health outcomes across diverse, global populations. The presentation will cover design and rationale, organization and progress of Consortium activities, methodological innovations, and initial Consortium findings and products. 

Overview of Presentation

• PRIMED is developing new PRS methods with a focus on equitable performance across diverse populations, including those that are admixed 

• PRIMED is exploring different approaches to incorporate genetic ancestry information into PRS development and evaluation  

• PRIMED is developing approaches to integrate non-genetic information such as social determinants of health with PRS to create comprehensive risk prediction models  

• PRIMED is leveraging the AnVIL cloud platform for consortium data sharing and collaborative analysis and is making analysis workflows for PRS methods and related analyses publicly available  

• The PRIMED common data model supports constructing cross-study datasets with harmonized genotype, phenotype, and genomic summary results data

• PRIMED built off of the NASEM report on Population Descriptors in Genetics and Genomics Research to develop recommendations and a data model to support the flexible and ethical use of population descriptors in PRS research 

A discussion of "A novel multivariable Mendelian randomization framework to disentangle highly correlated exposures with application to metabolomics"

A discussion of, "Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B"

The NIH’s All of Us Research Program is committed to collecting multiple types of health data from a million or more participants to create a diverse research resource that accelerates precision medicine. The All of Us Researcher Workbench is the free-to-access secure, cloud-based platform where registered researchers from both US-based and international intuitions access and analyze data using Python, R, or SAS coding languages. Currently the program has over 413,000 program participants with >245,000 whole genome sequence (WGS) samples and >314,000 genotyping arrays. Looking forward, we anticipate counts for both WGS and arrays to surpass 400,000 soon. The genomic data is combined with many types of phenotypic and auxiliary data types including electronic health records (EHR), survey data, physical measurements, and mobile health data (Fitbit). This session will 1) provide an interactive, guided demonstration of the public facing genomic tools, including the new PheWAS x GWAS data browser 2) provide an interactive, guided demonstration of our cloud computing platform, the Researcher Workbench 3) provide participants a hands-on opportunity to replicate a research study with new genomic data types including structural variant and long reads data and 4) conduct an interactive Q&A session to engage attendees about the All of Us Researcher Workbench and the novel technology implemented to conduct genomic analyses.

Please note, to participate in the interactive activities included in this workshop, please register for the platform. This process may take a few hours; registrants are strongly encouraged to complete this by November 15. Platform registration is optional but highly recommended.

ASHG's 2024 Annual Meeting was hosted in Denver, Colorado from November 5 - 9.

This package includes the following recordings:

Sessions

• Presidential Welcome & Address
• Featured Plenary Abstract Session I
• Biobank Scale Genetic Data Resources for Studying Complex and Rare Human Diseases
• Multimodal Approaches to Interpreting the Non-Coding Genome: Evolution, Functional Genomics, and Machine Learning
• Novel Aspects of Modeling Genetic Architectures of Complex Traits
• Presidential Symposium: Mendelian Traits: Thinking about Complexity in the World of "Simple" Genetics
• TOPMed 10-Year Anniversary: Ongoing Success and Future Directions
• From Variant to Function: Prediction and Understanding Variants Function
• Computational Methods for Causal Variant Prioritization
• Featured Plenary Abstract Session II
• How Do We Describe and Ascribe Clinical Significance to the Non-coding Genome?
• Complex Traits and Other Omics
• Exploring Omics: From Genomes to Microbiomes
• Featured Plenary Abstract Session III
• The Promise and Payoff of Human Genetics and Genomics: Paths from Bench to Bedside

ASHG Events

• Career Development Panel: How to Set Yourself Apart
• ASHG Policy Forum: The Next Frontier of AI/ML in Human Genetics/Genomics
• Addressing the Challenges of Polygenic Scores in Human Genetic Research

Workshops

• Workshop: Hidden Features of the UCSC Genome Browser
• Workshop: Getting started with biomedical and genomic data in the All of Us Researcher Workbench

A major goal of human genetics and genomics research is to understand, treat, and correct genetic diseases and alleviate patient suffering. However, moving discoveries from the bench to the bedside can be both daunting and lengthy. The 2024 Distinguished Speakers Symposium will feature leaders who have made important basic science discoveries and navigated the journey from discovery to drug development, clinical trials, and implementation of new therapies. Their work has given hope to patients and framed the ethics, policy, and communication around ground-breaking genetics and genomics research.

This session will be of interest to researchers and clinicians interested in learning about novel techniques to link large ancient DNA and modern datasets, and a novel technique for resolution of CNVs in complex regions of the genome that had previously been inaccessible. Attendees will then transition from basic science to clinical implementation through talks on how caQTL may help identify a layer of immune response regulation and enhance the prediction of complex disease risk, how genetic variation influences healthcare expenditure. The session will conclude with the results of a prospective pilot study to evaluate sequencing of a targeted set of genes for newborn screening in a diverse population.

Learning Objectives:
1. Recognize the genetic contribution to healthcare cost and poor health.
2. Illustrate a new computational tool for inferring genealogical relationships in modern and ancient DNA.
3. Resolving the remaining dark regions of the human genome.
4. Investigate the opportunities, challenges, and feasibility of DNA sequencing-based newborn screening.
5. Assess the contribution of chromatin accessibility differences to transcriptional immune variation across healthy individuals

Please note: This item is only available as part of the ASHG 2024 Annual Meeting Digital Pass.

This session highlights omics efforts (with a particular focus on sequencing in rare disease cohorts) from different institutions or large-scale projects, including efforts in Germany, the Netherlands, South Africa, and the United States.

Learning Objectives:
1. Summarize how research genomics can impact clinical care.
2. Recognize the challenges and solutions for integration of ultra rapid whole genome sequencing in hospitals.
3. Analyze the clinical utility of HiFi sequencing as a first tier clinical test and how it affects, patient management, and multidisciplinary collaboration.
4. Examine the complex interplay between the gut microbiome and geographical, lifestyle, genetic, and environmental factors in populations from low- and middle-income countries

Please note: This item is only available as part of the ASHG 2024 Annual Meeting Digital Pass.

This session features a collection of abstracts that employ multi-omic data to enhance our understanding of disease susceptibility. It emphasizes analyses involving mitochondrial DNA, leukocyte telomere length, and copy number variations. The abstracts extend beyond genomic data, incorporating various types of omics data to provide a comprehensive view of disease mechanisms. Notably, the session includes innovative approaches to mitochondrial DNA analysis. The speakers contributing to this session are notably diverse, further enriching the breadth of perspectives and expertise presented.

Learning Objectives:
1. Describe the utility of using genetic instruments at scale to disentangle age related disease mechanisms and provide strong support for previously reported relationships between telomere length and human health.
2. Explain the power of deep facial phenotyping and incorporating transcriptomics when analyzing whole genome sequencing data.
3. Recognize genetic factors leading to epistatic relationships of dosage sensitive genes.
4. Identify nuclear genetic loci associated with mitochondrial heteroplasmy.
5. Analyze the role of structural variants in disease.
6. Identify alignment patterns associated with complex genomic rearrangements

Please note: This item is only available as part of the ASHG 2024 Annual Meeting Digital Pass.

Genomic sequencing has been used within the clinic for over a decade, yet our understanding of clinically significant genetic variation is largely limited to the protein-coding genome. Although international efforts are underway to systematically interrogate which non-coding genetic variants are clinically significant, translating these findings into clinical medicine remains a challenge. In this session, we will synthesize the literature on hundreds of clinically significant non-coding genetic variants that are known to cause Mendelian conditions via the disruption of gene regulatory elements. In addition, we will discuss the barriers that exist for describing these non-coding variants, as well as ascribing clinical significance to them. Specifically, we will go over challenges that are encountered when assigning nomenclature to regions outside of what is commonly defined as a “gene”. We will then explore challenges with annotating and summarizing the functional impact and clinical significance of non-coding variants within clinically-facing databases like ClinVar. Finally, we will provide examples of syndrome discovery in the Genomics England 100,000 Genomes Project using the recent ACMG/AMP guidelines for interpretation of non-coding variants. The session will end with a panel discussion that will explore how we can overcome these barriers to translate ongoing efforts to annotate the function of the non-coding genome into clinical medicine.

Learning Objectives:
1. Recognize our current knowledge of how non-coding variants contribute to Mendelian conditions
2. Summarize the current naming strategies for elements of the human genome
3. Evaluate how existing guidelines can be adapted for classifying non-coding variation
4. Identify critical data elements to describe functional effects of a variant in a database

Please note: This item is only available as part of the ASHG 2024 Annual Meeting Digital Pass.