Genotype imputation is a key component of modern genetic association studies. The Michigan Imputation Server has thus far helped > 8,500 researchers from around the world to impute > 80M human genomes. This interactive workshop is intended for anyone interested in learning how to impute genotypes and to use the imputed genotypes, highlighting recent reference panels, including the multi-ancestry panel from the TOPMed program and a specialized HLA panel. 

A brief overview of imputation and the server will be followed by demonstrations and exercises, including: 

1) quality control and preparation of genetic data for use on the MIS with a special focus on diverse ancestries, chromosome X, and the HLA region; 

2) tracking runs and use of the application program interface for larger jobs; 

3) downloading data from the MIS and preparing data for genetic analysis; 

4) performing a GWAS using imputed data and interpreting results, taking into account imputation quality; 

5) using the additional features, such as the polygenic risk score calculation. 

We encourage participants to ask specific questions about their own projects. Workshop materials, including slides and example data sets, will be made available before the workshop and will remain online at the MIS website. We expect that this workshop will enable participants to generate high-quality imputed data sets and to effectively analyze them.

This session will feature 3 plenary talks presented at ASHG 2022. After each 15-minute talk there will be a 20-minute discussion session with additional panelists invited by the speaker, which will include Q&A from the audience.

Moderator: Kiran Musunuru, MD, PhD, MPH, ML

Speakers:

1. Hardip Patel, PhD: Australia's National Centre for Indigenous Genomics enabling the inclusion of First Nations peoples in genomics
   1. Panelists: Alex Brown, Bastien Llamas 
2. Rebecca Torene, PhD: Systematic analysis of nonsense-mediated decay escaping protein-truncating variants in 97,728 clinical exomes identifies new Mendelian disease genes
   1. Panelists: Scott Myers, Kevin Mitchell, Francisca Millan
3. Lingyan Chen, PhD: Novel therapeutic target discovery using circulating proteins in up to 42,000 UK Biobank participants through systematic Mendelian randomization and genetic colocalization
   1. Panelists: Joanna Howson, Cyrielle Maroteau, Lina Cai

This session will feature a variety of topic-based rooms you can join to network and interact with other attendees! 

There will be a  breakout room for each of the following scientific themes, each with a moderator to guide the conversation: 

• Clinical, Basic and Population Research: Mendelian Phenotypes
  • Moderator: Rose Yang, PhD, MPH, NCI/NIH
• Clinical, Basic and Population Research: Complex Traits
  • Moderator: Marina DiSteafano, PhD

Join this session to see 12 live poster talks, featuring all new content that was not presented at ASHG 2022. Each rapid-fire poster talk will be 5 minutes, followed by a brief Q&A with the presenter.

Moderator: Andrew Marderstein, PhD

Speakers: 

• Whole Exome Sequencing revealed spectrum of mutations associated with different myopathy in clinically suspected DMD patients of Bangladesh, presented by Tamannyat Binte Eshaque, M.Sc. Contact this speaker
• ANO7 alters prostate cell mitochondrial gene expression and metabolism, presented by Nasrin Sultana, MS Contact this speaker
• Polygenic scoring and causal inference of posttraumatic stress disorder using electronic health records highlights association with cardiovascular and respiratory traits, presented by Gita Pathak, PhD Contact this speaker
• Multiomic association studies and finemapping prioritises WDR6 and immune pathways to be associated with anorexia nervosa, presented by Danielle Adams, BS/BA Contact this speaker
• The utility of whole exome sequencing in atypical cases of heterogeneous neurological disorders, presented by Zafar Ali, PhD 
• A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss, presented by Farid Ullah, PhD 
• Identification of Hypomorphic SEL1L-HRD1 ER-associated Degradation Variants in Infants, presented by Huilun (Helen) Wang, PhD Contact this speaker
• Comprehensive characterization of genetic influences on plasma metabolome in a pediatric cohort, presented by Sek Won Kong, MD Contact this speaker
• 300 Billion Associations - Genetic architecture of 2,071 phenotypes in 658,582 individuals of diverse ancestry in the VA Million Veteran Program, presented by Anurag Verma, PhD Contact this speaker
• CRISPR-Cas9 depletion of high expression genes in human fibroblast samples increases the diagnostic potential for rare disease, presented by Rosario Corona, PhD Contact this speaker
• Deep convolutional and conditional neural networks for large-scale genomic data generation, presented by Burak Yelman, PhD Contact this speaker
• Fundamental limitations on the transferability of polygenic risk scores across human populations, presented by Kaiqian Zhang, MS

Digitalization of patient medical charts in the form of electronic health record (EHR) promotes precision medicine, which promises to be inclusive of a broad view of a person’s care. Disease genetics and pharmacogenomics (PGx) contributes to the success of precision medicine by providing genetic insights from preemptive care and disease diagnosis to drug prescribing recommendation. However, integrating genomics with EHR-linked health care systems is challenging. The ever increasing scale of EHR-linked health care systems ensues an increasing need for automated, computational annotation of genetic information to support fast-paced clinical decision making. This workshop will introduce several bioinformatics tools that facilitate automatic, computable annotation of genetic information. Computable representation of genetic variants is one bottleneck for accurate genetic curation and automatic annotation in analyses following clinical genetic tests. 

The first part of the workshop will focus on the Variation Representation Specification (VRS, pronounced “verse”), a recently published standard of the Global Alliance for Genomics and Health for the computable representation of biomolecular variation. VRS allows precise and federatable identification of genetic variants for downstream disease annotations and PGx annotations in EHR-linked health care systems. The associated VRSATILE (“versatile”) framework provides additional tools for representation of variation in computable genomic knowledge exchange. Exemplary applications of VRSATILE include knowledge and evidence retrieval across databases (e.g., functional and clinical databases) and computable representation of PGx variants. The second part of the workshop focuses on automating PGx annotations using PharmCAT (Pharmacogenomics Clinical Annotation Tool). PharmCAT is able to digest genetic information from VCFs, infer PGx named alleles and phenotypes, and generate detailed reports for clinical decision support. The capability of PharmCAT to automate PGx annotation makes it possible to translate clinical genetic test results to clinical decisions and actions at the scale of EHR-linked, large-scale health care systems. The workshop will provide an interactive, hands-on experience for participants and familiarize the audience with the latest bioinformatics tools that facilitate automation of genetic annotation and PGx annotation for large-scale, EHR-linked health care systems.

Advanced registration is required for this event. Please register now at this site. Registration is quick and free, and you can register anytime!

Upon registration, you will receive a confirmation email with your unique join link. Please join the session from your emailed confirmation link. It may take a few minutes for your link to be emailed to you, so we encourage you to register early so you don’t miss the start of the session.

If you have any trouble registering, please reach out to exhibits@ashg.org.

Title: Game Changed. Redefining Genomic Sequencing with HiFi Long Reads on Revio

Join us as three industry experts present on their work demonstrating a new gold standard in genomic and translational research with PacBio HiFi sequencing. Featuring presentations on methylation, complex medically relevant genes (CMRG) in dark regions, and SNM1/2 calling, we will take you on an exploration of what is possible and how you could apply their approaches to your own research and future breakthroughs.

• Speakers: 
• Edd Lee, Director, Human Genomics, PacBio (Introduction) 
• Warren Cheung, Bioinformatics Manager, Genomic Medicine Center, Children’s Mercy Hospital (Methylation) 
• Fritz Sedlazeck, PhD, Associate Professor, Human Genome Sequencing Center, Baylor College of Medicine (Dark Regions) 
• Xiao Chen, PhD, Principal Bioinformatics Scientist, PacBio (SNM1/2 Calling) 

*By registering for and attending this session, you consent to share your contact information with the sponsor of this session. Please view the disclaimer tab for more information.

Background: Current guidelines from the American College of Medical Genetics and Genomics and Association of Molecular Pathology (ACMG/AMP) are primarily designed for interpretation of genetic variants that impact protein-coding regions of the genome. We formed an expert panel to design recommendations for how to adapt the ACMG/AMP guidelines for variants in other genomic contexts (Ellingford et al. 2021).

Aim of the workshop: The aim of this interactive workshop is to outline key aspects of the recommendations and detail practical steps towards using the guidance in clinical settings. Users will utilize case examples to develop hands-on working knowledge of the modified guidelines. By the end of the workshop attendees will be able to:

• Understand changes to ACMG/AMP rules. Describe the key adaptations to the ACMG/AMP rules that are needed to effectively curate non-coding region variants and detail the extra considerations applicable when applying individual ACMG/AMP rules.

• Access datasets to define relevant non-coding regions. Understand how to access and interpret the key data and tools required to interpret non-coding region variants. Specifically, you will be familiar with how to access epigenetic data to define non-coding regulatory elements, and will know which in silico tools can be used to predict the pathogenicity of different variant types.

• Perform variant classification for a range of non-coding region variants. Know how to practically approach interpretation of non-coding region variants in your own setting having worked through a series of example curations

Expected prior knowledge / experience: This workshop is aimed at clinical scientists and genetics professionals with an active role in clinical variant interpretation. You will have a working knowledge of the current ACMG/AMP guidelines for small sequence variants.

Format: The workshop will be 90 minutes in length, with approximately 30 minutes spent on each of the three main aims outlined above. The first 30 minutes will be a talk on the background behind and the key aspects of the recommendations. The second 30 minutes will be a demonstration on how to access the tools and resources required to curate non-coding region variants, and the final 30 minutes will be an interactive work-through of example variant curations.

Reference: Ellingford JM et al. medRxiv. Dec 2021. doi:10.1101/2021.12.28.21267792v1

The recording of this session is now available. Please view in the Content tab. 

Title: Curating the Human Genome to Advance Early Identification of Rare Diseases: Meeting the Needs of Newborn Sequencing

The most critical challenge to making newborn sequencing a reality is genomic variant interpretation. Current approaches of interpreting variants one-by-one are impractical when it comes to screening a mostly healthy newborn population with whole genome sequencing. A radically different approach is needed to hit the time, cost, and throughput objectives for newborn screening of whole genomes. 

In this live discussion and demonstration, industry experts will show how a comprehensive, pre-curated list of causative variants can be used to rapidly screen for rare diseases and how a unique combination of AI-driven genomic technology and expert scientific review has emerged as the best and most viable way to curate the entire human genome. 

The speakers will describe Genomenon’s contributions to the BeginNGS™ initiative at the Rady Children’s Institute for Genomic Medicine, and how pre-curated classifications for every variant found in the scientific literature will be used to screen against over 450 genetic diseases at birth. They will then show how variant classification and supporting evidence is presented in the Mastermind® Genomic Search Engine to enable rapid assessment and identification of newborns at risk for developing a rare disease. 

The session will include a Q&A session around the implications of this technology on the future of rare disease screening and diagnosis. 

You will learn: 

• How a unique balance of AI and expert review creates a solid foundation of high-quality evidence to understand the genetic basis of a targeted disease 
• How the integration of data from the scientific literature with commonly used variant databases like ClinVar streamline accurate and timely diagnoses for patients 
• How this approach is being used to comprehensively access and classify every variant in the human genome, starting with newborn sequencing applications 

Speakers:

• Mark Kiel, MD, PhD, Chief Scientific Officer, Genomenon 
• Brittnee Jones, PhD, Director of Customer Success, Genomenon

*By registering for and attending this session, you consent to share your contact information with the sponsor of this session. Please view the disclaimer tab for more information.

This session will feature 3 plenary talks presented at ASHG 2022. After each 15-minute talk there will be a 20-minute discussion session with additional panelists invited by the speaker, which will include answering questions from the audience.

Moderator: Erica Davis, PhD

Speakers:

1. Endrina Mjuica, MD: Characterizing 54 type-2 diabetes candidate genes using CRISPR/Cas9, in vivo imaging and deep learning in zebrafish larvae 
   1. Panelists: Marcel den Hoed (Group Leader), Christoph Metzendorf (Researcher), Eugenia Mazzaferro (PhD student)
2. Scott Younger, MD, PhD: Rapid and scalable preclinical evaluation of personalized antisense oligonucleotides using organoids derived from rare disease patients
   1. Panelists: None
3. Yi Ding, MS: Polygenic score performance varies across the continuum of genetic ancestry in all human populations
   1. Panelists: Bogdan Pasaniuc

This session will feature a variety of topic-based breakout rooms you can join to network and interact with other attendees! There will be one room for each of the following themes: 

• Public Outreach & Education
• Social Implications & Ethics
• Career Transitions/Working in Industry

ASHG volunteer leaders who are experts in these areas will be leading the conversation in each space. Moderators for this session include:

• Arvind Kothandaraman, MA
• Justin Ideozu, PhD
• Stephanie Kraft, JD
• Kyle Brothers, MD, PhD
• Andrew Landstrom, MD, PhD
• Benjamin Kang, PhD
• Honey Reddi, PhD

This session features presentations by all 6 Trainee Research Excellence Award winners (formerly known as the Charles J. Epstein Award) from ASHG 2022. After each presentation there will be an opportunity for live Q&A. After all presentations there will be a 20-minute panel with all the winners.

Moderator: Latrice Landry MS, PhD, MSC

Speakers:

• Frederik Filip Vinggaard Stæger, MS: Genetics and integrated -omics of diabetes and associated metabolic disorders in diverse populations
• Marianne Lemée, MS: Navigating the complex genetic landscape of neurodevelopmental disorders
• Layla Siraj: Massively parallel variant characterization
• Nathan Nakatsuka MD, PhD: Populations evolving: Modeling genetic variation to understand evolutionary processes
• Yosuke Tanigawa, PhD: The methylome and transcriptome of complex traits
• Hai Nguyen, PhD: Let's talk about sex and its contributions to disease risk

Genome-wide association studies (GWAS) have now identified thousands of associated loci for complex diseases and related traits. But despite this success, in only a handful of cases so far have association data been translated to knowledge of causal variants, effector transcripts, biological networks, and potential therapeutic targets. Accelerating progress in this area requires 1) the large-scale integration of genetic association data with detailed, cell type-specific annotation of the epigenome, transcriptome, and proteome, and 2) open-access resources that make these integrated results easily interpretable for research scientists worldwide. 

In this workshop we will present one such resource, the Association to Function Knowledge Portal (A2FKP). Supported by NHGRI as a Genomic Community Resource, the A2FKP integrates high quality genetic and genomic datasets, bioinformatic method results, and expert-curated knowledge for multiple classes of disease, including metabolic, cardiovascular, immunological, pulmonary, musculoskeletal, and neurodegenerative disorders. The A2FKP is being developed in collaboration with the research communities in each of these disease areas. Epigenomic and functional results in the A2FKP are aggregated in collaboration with a sister resource, the Common Metabolic Diseases Genome Atlas (CMDGA). 

Attendees of this workshop will get an overview of the data underlying the A2FKP, will learn how to query the A2FKP both via the web interface and programmatically, and will practice using its interactive tools to form and test hypotheses about loci and genes of interest. Hands-on exercises will provide instruction in using the A2FKP to answer questions such as:

• Do current genetic and genomic data support the involvement of my favorite gene in a particular disease or trait?
• Which gene in a genetically associated locus is most likely to be causal for the associated trait?
• What is the overall genetic architecture of a particular complex disease? 
• For a variant of interest, what is the range of phenotypes with which it is associated? Does it lie within a region that has a potential tissue-specific regulatory role?
• How can I programmatically access the results in the A2FKP?

Attendees are also welcome to bring specific questions from their own research.

Title: ENPP1 Deficiency: The Life-long Burden of a Rare Genetic Mineralization Disorder

This session will review the pathophysiology, clinical presentation, and diagnosis of ENPP1 Deficiency, a genetic disorder with evolving phenotypes across the age spectrum. We will discuss new data from a comprehensive ENPP1 Variants curation project and highlight current and emerging therapies in development.

Speaker:

• Kurt Gunter, MD, Chief Medical Officer, Inozyme Pharma

*By attending this session, you consent to share your contact information with the sponsor of this session. Please view the disclaimer tab for more information.