ASHG 2021 Sessions

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The ASHG 2021 Annual Meeting was held virtually from October 18-22 2021. In this package, you can view member recommended sessions from the meeting.

For more information on the 2021 Annual Meeting, visit our website. 

  • Stakeholder Perspectives on Ethical and Social Implications of Using Clinical Polygenic Risk Scores through Embedded ELSI Research
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    Findings from ELSI studies examining returning clinical PRS across diverse populations.

    Many polygenic risk scores (PRS) have been published with an eye towards clinical implementation. However, little work has been done on the social and ethical considerations of calculating and returning PRS, particularly across genetic ancestral backgrounds. 

    This session reports findings from embedded ELSI studies examining social and ethical considerations of returning clinical PRS across diverse populations. The panel will advance our understanding of critical issues that must be addressed to maximize potential benefits of clinical PRS. Following an introduction to the topic, Maya Sabatello describes the views of patients, clinicians and IRB members about challenges translating PRS research into improved care and strategies to promote health equity. Broadening our understanding of variation in stakeholder views, Sabrina Suckiel highlights English- and Spanish- speaking patients’ perceptions of clinical utility of PRS, preferences regarding return of information and potential barriers to uptake. 

    The format of PRS results can impact patient and provider understanding of risk and responsiveness to corresponding recommendations. Anna Lewis discusses research on stakeholder preferences regarding various formats of return and the potential impacts on use and understanding. Finally, Ellen Clayton presents data on the role of patient education to ensure researchers understand racial/ethnic minority views on clinical PRS. Following discussion, closing remarks will highlight the utility of embedded ELSI projects within large-scale PRS or genomic studies and offer recommendations for future research. These studies, embedded in the Electronic Medical Records and Genomics (eMERGE) IV Network, were designed to inform return of actionable PRS for common complex diseases to patients and their healthcare providers.

    Recorded session from the 2021 virtual meeting. 

  • Global Genomics and Health Equity: Challenges and Opportunities
    Contains 1 Component(s) Recorded On: 10/20/2021

    This session will discuss ethnically diverse populations and health equity in genomic medicine.

    This session will focus on opportunities, challenges and ethical issues related to studying ethnically diverse populations to improve discovery and health equity in genomic medicine. Here we gather scientists from across the globe with experience in conducting genomic research in populations under-represented in human genetics research. 

    Speakers will address research on genetic risk factors for medical phenotypes of particular relevance to the study populations. We will also discuss ethical, social, and legal issues (ELSI) that arise when conducting genomic research in Indigenous communities, ways in which we can achieve more inclusive and equitable research, and ensure benefit sharing. We will have four 15-minute presentations followed by a 30 minute panel discussion. 

    Our session will start with a presentation discussing studies of pharmacogenetic variation in Indigenous peoples from South America and implications for personalized medicine in these populations. Our second speaker will describe results of a multi ethnic genome wide association study (GWAS) of Differentiated Thyroid Cancer (DTC) in Melanesians from New Caledonia and Polynesians from French Polynesian, two populations with the highest incidence of DTC worldwide. The speaker will illustrate the impact of genetic studies of DTC risk on community health in Oceanian populations. The next speaker will follow on the promising future for genetic discovery that can be achieved by studying African populations that have high levels of genomic and phenotypic diversity. This speaker will also illustrate how the study of ethnically diverse African populations has shed light on the genetic basis of hearing impairment, resulting in identification of multiple novel genes influencing hearing loss. Our last speaker will discuss ethical perspectives and the challenges of conducting genomic research in Indigenous populations from North America, the potential benefit for personalized medicine, and the importance of creating a partnership with Indigenous communities. 

    The panel discussion, which will include the two moderators and audience participation, will focus on how studies of ethnically diverse populations are of benefit to the global medical genetics community. We will further discuss ethical issue that arise from consequences of research that stigmatizes Indigenous communities and will touch base on principals of how to conduct research in minority and Indigenous populations in an ethical manner.

    Recorded session from the 2021 virtual meeting.

  • Cross-ancestry Genomic Research: Time to Bridge the Gap
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    This session will introduce recent efforts to level ancestry imbalance in genomic research.

    The success of genome-wide association studies (GWAS) in humans have yielded a wealth of clues about the molecular basis of many common human diseases. In addition, polygenic risk scores (PRS) for a variety of traits are increasingly becoming accurate enough to be useful for clinical practice, realizing the longstanding goal of personalized medicine. However, data collection continues to be predominantly imbalanced towards individuals of European ancestry, and it is abundantly clear that methods developed in one human ancestry group do not perform well in other ancestry groups, limiting their utility and exacerbating already severe health disparities. The speakers in this session will introduce recent efforts to level ancestry imbalance in genomic research, including the formation of large collaborative efforts and the development of novel statistical methods.

    Recorded session from the 2021 virtual meeting.

  • Insights into the Molecular Basis of Craniofacial Development
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    Speakers discuss the molecular basis of craniofacial development.

    Platform sessions are abstract driven sessions with 6 talks per session. These talks are 10 minutes in length and are cross-topical in nature to represent the broad discipline our field of genetics and genomics represent. After each talk, there will be a 5-minute Q&A with each speaker. For information on each individual session, please view the "Details" tab. 

    Recorded session from the 2021 virtual meeting.

    HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations

    Structural variants (SVs) such as insertions, deletions duplications, translocations and inversions, are associated with human disorders. SVs can affect protein coding sequences as well as gene regulatory elements. However, SVs disrupting protein coding sequences that also function as cis regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the Histone deacetylase 9 (HDAC9) protein coding sequence are associated with disruption of TWIST1 regulatory elements that reside within HDAC9 sequence. Using epigenetic marks and in vivo enhancer assays, we characterized six craniofacial TWIST1 enhancers located in the TWIST1-HDAC9 locus. Based on SVs within the HDAC9-TWIST1 locus, we defined the 3' HDAC9 sequence (~500Kb) as a critical Twist1 regulatory region. By deleting Twist1 enhancers within the Hdac9 protein coding sequence in mice (eTw5-7Del/Del), we showed that Twist1 expression was decreased, resulting in smaller sized and asymmetric skull and polydactyly. Furthermore, deletion of a Ctcf site (CtcfDel/Del) within the Hdac9 protein coding sequence, disrupted Twist1 enhancer-promoter interactions and altered Twist1 expression which led to deformed skull and hindlimb polydactyly, resembling Twist1+/- mouse phenotype. Deletions of Twist1 regulatory elements altered the distinct anterior\posterior expression patterns of Shh pathway genes, including Hand2 and Alx4. Using UMI-4C, we demonstrated that both enhancers and Ctcf site regions interact with Twist1 promoter region. These interactions are depended on the presence of both regulatory regions, indicating a specific chromatin conformation of Hdac9 in regulating Twist1 expression. Finally, a large inversion of the entire Hdac9 sequence (Hdac9INV/+) that does not disrupt Hdac9 expression but rather repositions Twist1 regulatory elements showed a decrease in Twist1 expression that led to subtle craniofacial phenotype and hindlimb polydactyly. Thus, our study elucidated essential components of TWIST1 transcriptional machinery that reside within the HDAC9 sequence, suggesting that SVs, encompassing protein coding sequence, such as HDAC9, could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene, such as TWIST1. 

    Ramon Y Birnbaum
    Ben Gurion University

    Kate Wilson Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation TrustDe-Novo Mutations identified in Nonsyndromic Cleft lip/Palate Families from Africa

    Background: Despite successes in the investigation of de novo mutations (DNMs) in the etiology of some birth defects (autism, congenital heart defects), only a limited number have been reported for nonsyndromic cleft lip with or without cleft palate (NSCL/P), the most common craniofacial birth defect. To identify high impact DNMs controlling risk of NSCL/P, we conducted whole genome sequencing (WGS) analyses of case-parent trios from an understudied population.
    Method: A total of 150 nsCL/P African case-parent trios were sequenced for this study. Each trio comprises an affected child (with nsCL/P) and unaffected parents and were recruited from Ghana and Nigeria. Saliva samples were collected from these individuals and their genomes were sequenced from extracted DNA. After quality control, we screened the genomes of the remaining 130 trios for high impact DNMs possibly contributing to risk of nsCL/P. We used bioinformatic prediction tools to identify those mutations predicted to damage and affect the protein structures and functions.
    Results: We identified 110 potential pathogenic DNMs. These include novel loss of function (LOF) variants in TTN, MINK1 and ARHGAP10 genes; and missense variants in DHRS3, TULP4, SHH, TP63, FKBP10, ACAN, RECQL4 and KMT2D. These variants are predicted to be damaging and are among the most deleterious (top 1% ) mutations in the human genome. Experimental evidence in published works showed TTN, SHH, TP63, FKBP10, ACAN, RECQL4 and KMT2D genes are involved in facial development and are involved in the etiology of syndromic CL/P. While DHRS3, SHH and TP63 contribute to the risk of nsCL/P. Interestingly, our SHH de novo variant p.Ser362Leu has been reported to cause holoprosencephaly 3 (HPE3), a syndromic form of CL/P. Damaging mutations in the DHRS3 gene affects retinoic acid signaling during embryogenesis which causes cleft palate. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. MINK1 plays a role in cell-cell adhesion and migration, and causes abnormal tooth morphogenesis in mice. Our gene-set enrichment analysis identified additional genes that are important in palatal development. These include DLX6 and EPHB2 and they both harbored novel damaging DNMs.
    Conclusion: Our WGS adds to the available data on Africa population (a historically underrepresented group in genetics study) and has identified novel pathogenic de novo variants that may contribute to the developmental pathogenesis of NSCL/P. These findings demonstrate the power of WGS analysis of trios for discovering potential pathogenic variants. 

    Waheed Awotoye
    Iowa Institute for Oral Health Research, University of Iowa

    Identification of novel molecular pathways in syndromic orofacial clefting

    Background: Syndromic orofacial clefting (OC) accounts for 30% of cleft lip and/or palate. An updated review of molecular pathways associated with syndromic OC is unavailable. The Deciphering Developmental Disorders (DDD) study provides a source of quality data to assemble this information. The Genomics England PanelApp is a publicly available database of curated virtual gene panels and is a valuable reference tool for genes associated with syndromic OC.
    Aim: To investigate molecular pathways associated with syndromic OC by reviewing the results of exome sequencing (ES) and exon-arrayCGH in a large cohort of patients with syndromic OC.
    Methods: Patients with the HPO terms ‘cleft’ and ‘bifid uvula’ were identified through a Complementary Analysis Project within the DDD study. Possible diagnostic variants were identified by automated variant filtering and manual review. Single nucleotide variants (SNVs) within known disease-causing genes and copy number variants (CNVs) were classified according to the ACMG guidelines, the ACGS Best Practice Guidelines and consensus opinion. Functional analyses of identified genes were performed within STRING, Cytoscape and MCODE. Associated phenotypes were explored using the International Mouse Phenotyping Consortium. Gene expression analyses were performed within GENE2FUNC.
    Results: 603/13612 (4.4%) patients were identified of whom 453/603 (75.1%) had trio ES. Pathogenic (P) or likely pathogenic (LP) variants were identified for 220/603 (36.5%) patients in 124 known disease-causing genes with SATB2 the most common (16/220, 7.3%). 23/220 (10.5%) patients had a P or LP CNV of partial or full contribution to their phenotype. 35/124 genes fulfilled criteria to be added to the PanelApp ‘Clefting’ panel, increasing the size of the current panel by 23.8%. Gene ontology and pathway analyses identified novel molecular networks for syndromic OC which were distinct from those in non-syndromic OC. Gene expression analyses and investigation of knockout phenotypes also showed a distinction between syndromic and non-syndromic OC. Pathway and expression analyses showed an enrichment of genes associated with intellectual disability (FDR=2.8x10-33), RNA metabolism (FDR<3.5x10-21), transcription (FDR<2.3x10-20) and chromatin organisation (FDR=1.03x10-11).
    Conclusion: This study demonstrates the utility of ES and CNV analysis for patients with syndromic OC and increases the diagnostic rate for this patient cohort. It also highlights novel molecular pathways specific to syndromic OC and enhances our understanding of lip and palate development. 

    RERE deficiencycontributes to the development of orofacial clefts in humans and mice

    Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7, and GRHL3. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH), but have not been shown to cause orofacial clefting. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate, and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox;Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of cleft palate in individuals with proximal 1p36 deletions and NEDBEH, and that RERE expression in cranial neural crest cells and their derivatives is required for normal palatal development. 

    Bum-Jun Kim
    Molecular & Human Genetics, Baylor College Medicine

    Single cell transcriptomics-directed investigation of de novo mutations and rare inherited genetic variants in cleft lip and palate

    Cleft lip and palate (CL/P) is one of the most common congenital anomalies. The etiology of CL/P is complex with both environmental and genetic risk factors. While previous studies have identified several CL/P-associated genes or regions, only a fraction of all cases can be clearly attributed to specific genes. Additional genetic causes may be due to rare inherited variants (RIVs) or de novo mutations (DNMs) in simplex CL/P cases. To investigate this further, we performed single cell RNA sequencing on epithelial cells of the lambdoidal junction (λ) from gestational day (E)10.5 wildtype mouse embryos at the point of upper lip fusion. We identified six cell clusters, and using the top 150 differentially expressed genes from each, we carried out targeted evaluation of both DNMs and RIVs in whole genome sequences from 756 CL/P case-parent trios of Asian, Latino, and European ancestry. For each cluster we analyzed enrichment of nonsynonymous, loss-of-function (LOF), and protein altering (nonsynonymous + LOF) DNMs. Of these, the olfactory epithelium cluster was enriched for protein altering (p=0.005) and the periderm cluster was enriched for nonsynonymous variants (p=0.005). We then evaluated exonic RIVs as defined by a minor allele frequency of <0.05% in gnomAD. A total of 2,976 variants were identified, with subsequent filtering for gene and variant specific constraint resulting in 445 variants of interest in 109 genes. Among these were several CL/P risk associated genes, including IRF6, TFAP2A, and GRHL3, all of which contained both DNMs and RIVs, suggesting other genes identified via this method may also be significant in risk for CL/P. Although all clusters were evaluated, the λ-fusion effector cluster was of specific interest given its critical role in prominence fusion during normal craniofacial development. This cluster harbored variants of interest in 31 genes, a higher percentage than other clusters (23% vs. 9-19%). Further, gene ontology revealed a group of 14 genes enriched for terms related to transcription and, interestingly, both negative regulation of epithelial cell proliferation (FDR 0.015) and positive regulation of mesenchymal cell proliferation (FDR 0.049). Among this group was transcription factor ZFHX3, which contained the most variants including loss-of-function DNMs and RIVs; thus, it remains of high interest for novel CL/P risk association. This investigation illustrates the benefit of integrating genomic technologies to prioritize and identify novel genetic associations with risk to CL/P. Continued evaluation focused on gene interactions and pathways represented by these variants may further elucidate CL/P etiology. 

    Kelsey Robinson
    Emory University

    A novel 3 MB deletion on 6p24 removes distant neural-crest enhancers controlling TFAP2A resulting in mild Branchiooculofacial syndrome in a multiplex family with orofacial clefting

    In a previous effort to characterize large copy number variants as genetic risk factors for orofacial clefting (OFC) following a genome-wide association study, we identified a novel 3 Mb deletion on 6p24 in three affected members of the same family from Colombia. The reported pedigree had a dominant inheritance pattern and included 5 individuals with OFC. All affected family members carried the deletion, which was inherited from the proband’s unaffected grandmother. Supporting the pathogenicity of this deletion, exome sequencing of this family found no segregating single nucleotide variants in OFC candidate genes. The 3Mb deleted region included 12 genes, none of which are strong OFC candidates and a 840 kb gene desert. We observed that the 3’ breakpoint of this deletion occurred within a large non-coding region directly adjacent to the important developmental transcription factor TFAP2A. TFAP2A loss of function is one of the primary genes associated with Branchiooculofacial syndrome (BFOS) that includes OFC in conjunction with branchial and ocular abnormalities. Affected members of this family display OFC, broad nasal root, and slight hypotelorism characteristic of BFOS. Cell type-specific enhancers in the genomic region directly flanking TFAP2A have been previously implicated in a subset of BOFS patients, however these enhancers remain intact in this family.We hypothesized that this deletion contains additional regulatory elements of TFAP2A, resulting in attenuated expression of this gene and a milder form of BOFS. To address this hypothesis and predict enhancer-gene interactions at this region, we used an activity by contact model (ABC-Enhancer) to integrate ChIP-seq based chromatin state annotations, chromosome conformation (Hi-C), and gene expression (RNA-Seq) from primary human craniofacial tissues and a culture model of cranial neural crest cells (CNCCs). We identified closely clustered, strong enhancer states that were predicted to have interactions with TFAP2A over a distance of greater than two megabases. To validate these predictions in vivo, we used CRISPR-Cas9 in human embryonic stem-cells to create homozyguous deletions of a 25kb region encompassing the strong enhancer segments. We differentiated these lines to CNCCs and compared gene expression and proliferative capacity to wildtype. We found this region is essential for cell viability during CNCC differentiation and differential gene expression analysis revealed substantial effects on TFAP2A expression. In summary, we identified a region within the inherited deletion that regulates TFAP2A gene expression and could contribute to the mild BOFS phenotype in this family. 

    Tara Yankee
    Department of Genetics and Genome Sciences, UConn Health Graduate Program in Genetics and Developmental Biology

  • Genomics in Africa Coming of Age
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    Speakers discuss genomics in Africa.

    Platform sessions are abstract driven sessions with 6 talks per session. These talks are 10 minutes in length and are cross-topical in nature to represent the broad discipline our field of genetics and genomics represent. After each talk, there will be a 5-minute Q&A with each speaker. For information on each individual session, please view the "Details" tab. 

    Recorded session from the 2021 virtual meeting.

    Revisiting the out of Africa event with a deep learning approach

    Anatomically modern humans evolved around 300 thousand years ago in Africa. Modern humans started to appear in the fossil record outside of Africa about 100 thousand years ago though other hominins existed throughout Eurasia much earlier. Recently, several researchers argued in favourof a single out of Africa event for modern humans based on whole-genome sequences analyses. However, the single out of Africa model is in contrast with some of the findings from fossil records, which supports two out of Africa, and uniparental data, which proposes a back to Africa movement. Here, we used a deep learning approach coupled with Approximate Bayesian Computation and Sequential Monte Carlo to revisit these hypotheses from the whole genome sequence perspective. Our results support the back to Africa model over other alternatives. We estimated that there are two successive splits between Africa and out of African populations happening around 60-90 thousand years ago and separated by 13-15 thousand years. One of the populations resulting from the more recent split has to a large extent replaced the older West African population while the other one has founded the out of Africa populations.

    Mayukh Mondal
    Institute of Genomics, University of Tartu

    An analysis of population copy number variation in sub-Saharan African genomes


    Introduction Copy number variation (CNV) is responsible for a large component of normal human variation and has been implicated in the cause/genetic aetiology of several rare diseases. Population reference databases containing CNV information from all global populations is critical in disease genetics research, but current resources lack diversity, especially from the African continent. This makes such databases of limited use in studies looking at genetic diseases in African individuals. This study therefore aims to address this knowledge gap by producing a map of CNV using whole-genome data from several, previously unstudied African populations
    Methods 1027 high coverage whole genome sequences obtained from individuals across west, central, southern and east Africa, were analysed using Manta and Graphtyper2. Additionally, 919 of the samples were also analysed using Genome STRiP to detect multi-allelic CNV. Quality control specific to each tool was performed in order to achieve high quality variant call sets.
    Results 56 816 CNVs were detected by the Manta pipeline, consisting of 44 671 deletions and 12 145 duplications. Due the ability of Manta to detect small variants (<100bp), we are able to describe this previously less studied class of variants in an African cohort. 25% of the variants detected by Manta were <100 bp and 40% of these were common variants at >5% allele frequency. 50% of these variants are novel compared to 27% of the remaining variants >100bp. Overall, 32% of the variants identified were novel. A comparison between central, west, east and southern African regions yielded a number of variants unique to each region. We find deletions tend to have lower allele frequencies compared to duplications. The majority of variants were found in the non-coding genome, with only 8% of variants overlapping coding transcripts. An additional 5% of variants overlapped regulatory features. Genome STRiP detected 3991 multi-allelic variants with 99% having a copy number between 3-20. There were also variants with copy numbers greater than 20, some of which appear to be incidences of excessive runaway duplications not previously described.
    Conclusion The amount of novel variation found demonstrates the importance of including African individuals from multiple African regions when producing reference databases and the rich genomic diversity of African genomes. Work is currently being performed to combine the full Genome STRiP and Manta call sets to produce a robust combined dataset. The variant database produced in this study will provide a valuable resource as a reference of normal CNV for the study of diseases in African populations.    Emma Wiener

    Division of Human Genetics, National Health Laboratory Service & School of Pathology, Faculty of Health Sciences, University of Witwatersrand

    Integrative genomic analyses identify key interethnic differences in immune response to malaria

    Host responses to infection with the malaria parasite P. falciparum vary between individuals for reasons that are poorly understood. Here we reveal metabolic perturbations as a consequence of malaria infection in children and identify an immunosuppressive role of endogenous steroid production in the context of P. falciparum infection. We perform metabolomics on matched samples from children from two ethnic groups in West Africa, before and after infection with seasonal malaria. Analyzing 306 global metabolomes we identify 92 parasitemia-associated metabolites with impact on the host adaptive immune response. Integrative metabolomic-transcriptomic and causal mediation- moderation analyses reveal an infection-driven immunosuppressive role of parasitemia-associated pregnenolone steroids on lymphocyte function and the expression of key immunoregulatory lymphocyte genes in the Gouin ethnic group. In children from the less malaria-susceptible Fulani ethnic group we observe opposing responses upon infection, consistent with the immunosuppressive role of endogenous steroids in malaria. These findings advance our understanding of P. falciparum pathogenesis in humans and identify potential new targets for antimalarial therapeutic interventions. 

    Youssef Idaghdour
    New York University Abu Dhabi


    GWAS of complex traits in a multi-population African cohort

    The diversity among present-day African populations is the result of a deep and complex history of admixture, migrations, and regional adaptations to local environments and diseases. Little is known about the impact of this evolutionary history on the genetics underlying complex traits. Here I present recent work on genetic associations for a panel of anthropometric, cardiovascular, and metabolic biomarker measurements paired with dense genotyping data. For some traits, the variation among populations is expected to reflect local adaptations, such as short stature in western Cogo rainforest hunter-gatherers. The study cohort of several thousand individuals is drawn from an ancestrally diverse set of populations from western, eastern, and southern sub-Saharan Africa. Populations include current or recent hunter-gatherers, traditional agriculturalists, and semi-nomadic pastoralists, from rural regions of Cameroon, Nigeria, Ethiopia, Kenya, Tanzania, and Botswana. For many of these traits, this marks the first genotype/phenotype analysis to include these ethnic groups. The high degree of population structure presents both challenges and opportunities for genetic analysis. Genetic structure analysis indicates genetic clustering by geographic location, language family, and regional hunter-gatherer lineages. Examples include the hunter-gathers from the Serengeti, western Congo, and Kalahari, and clusters that correlate with Niger-Congo, Afroasiatic, and Nilo-Saharan language families. We observe substantial population-level variation for many traits, such as height, skin pigmentation, and blood pressure. The proportion of the trait variance that is due to the genetic population structure varies by trait and tends to be greater for anthropometric traits like height and skin pigmentation than for metabolic biomarkers like LDL. From genotype/phenotype association tests we find numerous independent associations at genome-wide significance for several traits, including circulating triglyceride levels and BMI. The population structure of the total additive genetic effects is also examined. European GWAS associations replicate poorly in this African cohort, while associations discovered in the African cohort show comparatively better replication in Europeans. 

    Matthew Hansen
    Univ Pennsylvania

    Genotype-by-infection interactions: Single cell RNASeq profiling of in-vivo host immune response to malaria reveals cell type and infection-specific eQTLs

    The disease burden of malaria remains a significant global public health challenge. Plasmodium falciparum is responsible for more than 99% of malaria cases in Africa and for >400,000/year malaria-related deaths worldwide. Inter-individual differences in susceptibility to malaria is multifactorial and has a significant heritable component but our understanding of the effect of infection on gene regulation of immune response at the transcriptional remains very limited. Here we use longitudinal matched sampling, single cell RNAseq profiling of PBMCs and whole-genome sequencing data of malarial children before and after natural P. falciparum infection in Banfora, Burkina Faso, West Africa. In total, we generated ~90,000 single cell RNASeq profiles and identified PBMC cell types affected by infection. Single cell RNASeq eQTL analysis revealed cell type specific eQTLs and genome-wide significant genotype-by-infection interaction effects implicating key immune genes. These results provide the first genome-wide picture of host in vivo regulatory variation events in malaria at the single cell level and highlight the implication of regulatory interaction effects in modulating host immune response in-vivo. 

    Odmaa Bayaraa
    New York University Abu Dhabi


    Returning secondary genetic findings: Provider perspective in Africa

    Objective: Previous research has shown that lack of resources and knowledge significantly impact the return of genomic test results. However, not much is known about the level of expertise and knowledge of clinicians providing cleft care in Africa on genetic diseases, despite the vast genetic diversity in this population.
    Methods: Providers in participating cleft-craniofacial clinics in Ethiopia, Ghana, and Nigeria were sent the link to a 63-question online survey. This survey assessed the providers' experience with genetic testing, genetics education and return of genetic results, provider knowledge, clinician comfort with returning results, available resources to assist with genomic findings, and potential barriers.
    Results: As of June 2nd, 2021, 246 providers completed the survey. Only 2% had been involved in the delivery of Exome or Genome sequencing; 78.6% had no formal genetic education, 49.6% agreed that all secondary findings should be disclosed to patients. Regarding the comfort level, 89.4% were somewhat to extremely comfortable discussing genetic risk factors with patients, and 81.8% were somewhat to extremely comfortable with returning genetic results. Sixty-three percent believed that resources were currently available to enable them to access needed genetic information.
    Conclusion: Providers were aware that genetic testing could help in the clinical management of diseases from the returned responses. However, the lack of knowledge about genomic medicine, uncertain clinical utility, and lack of available resources were cited as barriers that significantly impacted incorporating genetic testing into their practice. Data collection is ongoing and will continue till July 31st, 2021. This is the first Ethical, Legal, and Social Implications (ELSI) study to document the knowledge and comfort level of cleft providers in Africa. This study will help determine the most beneficial information to equip providers with the return of secondary genetic findings. 

    Abimbola Oladayo
    University of Iowa

  • Global Perspectives and Initiatives for Large-Scale Genomics
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    Speakers discuss global perspectives and initiatives for large-scale genomics.

    Platform sessions are abstract driven sessions with 6 talks per session. These talks are 10 minutes in length and are cross-topical in nature to represent the broad discipline our field of genetics and genomics represent. After each talk, there will be a 5-minute Q&A with each speaker. For information on each individual session, please view the "Details" tab. 

    Recorded session from the 2021 virtual meeting.

    Trans-ancestry imputation and exome sequencing of more than 1 million individuals identifies genetic variation protecting against SARS-CoV-2 infection and predicts individuals at risk for severe COVID-19 outcomes

    COVID-19 symptoms vary widely, ranging from asymptomatic in some patients to fatal in others. Elucidating the host genetics of COVID-19 holds the potential for understanding both susceptibility to SARS-CoV-2 infection as well as heterogeneity in patient presentation and outcome. Prior work focused on identifying common variants associated with COVID-19 susceptibility and severity, but little has been done to explore the entire allele frequency spectrum of genetic variation, from common to rare exonic variants. Here, we present the largest trans-ancestry exome sequencing study of COVID-19 to date in 586,713 individuals, with a larger set of 1,012,636 individuals with imputed data across 7 studies and 5 continental ancestries.
    Through exome sequencing of 21,820 COVID-19 cases and 564,893 controls, we did not identify any rare variants after Bonferroni correction (P<9.6e-10). Burden tests identified three genes tentatively associated with COVID-19: DISP3 (P=2e-8; OR=1.8±0.3), MARK1 (P=3e-9; OR=38.4±16.9), and TLR7 (P=4e-8; OR=4.5±2.2). Despite having a 100x larger sample size, we could not replicate a previous reported role for rare variants in the interferon pathway (P=0.59).
    Our larger GWAS of 56,841 cases and 955,795 controls found 11 loci (P<5e-8). Most notably, we identified a strong protective association amongst SARS-CoV-2 infected cases for rs190509934 located 60bp upstream of ACE2, the primary cell receptor for the SARS-CoV-2 spike protein (P=4.5e-13; OR=0.6±0.08; EUR MAF=0.003). Using RNA-seq, rs190509934 reduced ACE2 expression by 39% (P=3e-8), supporting the hypothesis that reduced ACE2 expression protects against SARS-CoV-2 infection.
    Lastly, we developed a polygenic risk score (PRS) to predict hospitalization and severity of COVID-19. Among those of European ancestry, individuals with the top 10% PRSs are 1.8-fold more likely to be hospitalized (P=6e-11) and 1.58-fold more likely to be placed on a ventilator or die from COVID-19 (P=7e-10). These associations hold in other non-European populations (albeit with decreased power) and after accounting for known clinical risk factors.
    Our data represents the most comprehensive survey of common and rare exonic variation associated with COVID-19 identifying new loci and polygenic risk scores that predict severity of COVID-19. 

    Jack Kosmicki
    Regeneron Genetics Center

    Rare variant analyses in 239,395 whole exome and whole genome sequenced participants of the UK Biobank reveals novel genetic associations with renal function and chronic kidney disease

    Genome-wide association studies have identified common genetic variants associated with chronic kidney disease (CKD), but the burden of rare loss-of-function (LoF) or pathogenic/likely pathogenic (P/LP) variants has not been well characterized. We performed gene-/region-based and variant association analyses for 5 renal function biomarkers (eGFR estimated from serum creatinine and/or cystatin-C, BUN, UACR) and 5 CKD endpoints (ESRD and stage4/5 CKD, CKD defined by biomarkers and/or diagnoses from NHS data, Cystic) in 239,395 UKB participants of genetically-assessed European ancestry and with whole exome (WES, n=171,172) or whole genome sequencing (WGS, n=121,019). For each trait, we fit a genome-wide regression model and tested for association using REGENIE V2.0, adjusting for age, sex, 10 principal components of ancestry, assessment center and BMI, where appropriate. For gene-based analyses, we generated 15 models to collapse ClinVar-classified P/LP, VEP(LOFTEE)-predicted putative LoF and deleterious variants predicted by 16 in silico scores (SIFT, Polyphen, BayesDel, etc.) from dbNSFP 4.1c. The WGS data further enabled annotation of promoter/enhancer variants, which were incorporated into collapsing models for gene-based association. In participants with WES, we identified 30 and 11 genes associated with ≥2 biomarkers and ≥1 CKD endpoint across collapsing models (FDR<0.05), respectively. PKD1/2, COL4A3/4, CUBN, IFT140 were associated with both biomarkers and CKD. Association analyses also highlighted other genes including: COL4A1, CST3, LAMC1, LRP2, SLC22A2, SLC34A3, SH2B3. Variant-level analyses further informed impact on protein, e.g. the SLC22A2 association signal was mainly driven by a frameshift (rs8177505) with lowering effects on eGFR (p=1.2e-27, beta=-6.2, MAF=0.12%). Exome-wide variant analyses revealed 25 genes (eg. PDILT-UMOD) with variant associations (p<5.0e-8) with >3 biomarkers or ≥1 endpoint, including 2 that were also implicated from the gene-based analyses (COL4A4 and CUBN). Analyses of WGS allowed for sequence level validation of exome derived findings and the identification of additional variants not captured in WES. This study provides a framework for the assessment of the genetic landscape of kidney disease. The results validated known genes and identified potential novel associations with renal function. 

    Shuwei Li
    Janssen

    Novel genetic associations for rare diseases with GWAS and trans-ethnic analysis of self-reported medical data

    Nearly 7000 rare diseases are known, and though each disease affects a few people, the total population prevalence of rare diseases is estimated to be 3.5-5.9%. A key challenge in the study of rare disease genetics is assembling large case cohorts for well-powered studies. Here we demonstrate use of large-scale self-reported rare disease data, combined with genetic data collected through the 23andMe direct-to-consumer platform, to study 33 rare diseases and identify genetic associations through GWAS. We developed web-based questionnaires, and gathered self-reported data on rare diseases from a cohort of over 1.6 million genotyped research-consented individuals. To reduce mis-reporting and maximize coverage, we used an autocomplete mechanism including 7000 rare diseases. We validated the approach through simulations and replication of known rare disease associations. In simulations based on genotypes from 4,957,230 European individuals, we show that GWAS can recover genome-wide significant associations in monogenic rare diseases for a variety of architectures. In rare diseases with known genetic associations, we reidentified 29 associations at a genome-wide significance level (p-value < 5e-8) with a diverse range of minor allele frequencies (minimum MAF=0.0001, maximum MAF=0.487) and effect sizes for the risk allele (minimum OR=1.24, maximum OR=273.15). We performed the first GWAS in European ancestry for Duane retraction syndrome, vestibular schwannoma and spontaneous pneumothorax, and report novel genome-wide significant associations for these diseases. For Duane retraction syndrome, an eye movement disorder, we found two independent associations near the OLIG1 and OLIG2 genes, knockdown of which causes a similar phenotype in mice. For vestibular schwannoma, we find a single association near the CDKN2A and CDKN2B genes, which are associated with many other cancers. We found three novel associations for spontaneous pneumothorax, two of which are also associated with lung function phenotypes. We replicated these associations in the UK Biobank and found that 3 of 5 replicated with p < 0.05, and all 5 had the same direction of effect. Trans-ethnic mixed-model analyses, including individuals of all ancestries, found the same associations with comparable or increased significance. Our results show that self-reported rare disease data is a viable method for discovering genetic associations for rare diseases. With increasing sample size and diverse imputation reference panels, we may also be able to study rare diseases more widely in multiple populations and improve our understanding of the trans-ethnic genetic architecture of these diseases. 

    Suyash S Shringarpure
    23andMe

    Common and rare variant analysis of 21K psoriasis cases and 623K controls identifies novel, protective associations in several genes in the type 1 interferon pathway

    Psoriasis is a complex autoimmune disease resulting in chronic inflammation and hyperproliferation of the skin. The aberrant immune response associated with psoriasis is mediated by pathogenic T cells, which are activated, in part, by type 1 interferons (IFNs). Prior large-scale analyses of psoriasis cases focusing on common genetic variants have implicated >63 loci, including genes in the IFN signaling pathway. However, large-scale analysis of rare exonic variation is lacking.
    To study the contribution of both common and rare variants to psoriasis risk, we performed whole-exome sequencing and meta-analysis of 20,810 psoriasis cases and 623,159 controls of EUR and AFR ancestry across 6 cohorts. Common variant analysis replicated 44 significant and independent associations in known psoriasis loci, including IL23R, TYK2, IL12B, HLA-C, and DDX58, among others. Rare-variant gene-burden analysis of putative loss-of-function (pLoF) and/or predicted-deleterious missense variants (<1% AAF) identified significant and novel associations in 5 genes, including 3 genes in the IFN pathway. These include protective pLoF associations for IFIH1 (OR=0.74 [0.68, 0.81], p=4.1E-12), which encodes a pathogen sensor that activates IFN production, and TRIM65 (OR=0.63 [0.50, 0.79], p=4.8E-5), which encodes a ubiquitin ligase that binds and activates IFIH1. We find the protective TRIM65 association is driven by a rare, predicted-deleterious missense variant (rs202175254, AAF=0.1%) in the IFIH1-TRIM65 binding domain. Further, we find a nominally significant, protective association for the burden of rare pLoFs in DDX58 (OR=0.76 [0.49, 0.89], p=6.7E-3), which encodes a second pathogen sensor that activates IFNs. This DDX58 protective pLoF association helps confirm direction of effect at this known psoriasis locus.
    Consistent with inhibition of IFNs being protective in psoriasis, we also found a significant and novel gene-burden association between increased odds of psoriasis and pLoFs in ADAR (OR=2.29 [1.68, 3.12], p=1.4E-7), which encodes a protein that suppresses IFNs and in which partial LoFs have been associated with Aicardi-Goutières syndrome, an inherited disorder that features over-production of IFNs.
    Collectively, these results represent the largest rare-variant exome-sequencing analysis of psoriasis, to date. Future experiments will characterize effects of these pLoFs on protein expression and/or function, and further analysis will determine whether an IFN gene signature can identify a clinically-relevant subset of psoriasis patients who would therapeutically benefit from IFN inhibition. 

    Julie Horowitz
    Regeneron Genetics Center

    Investigating genetic and phenotypic associations for 168 blood metabolites in 120K UK Biobank participants

    In this study, we accessed the large-scale metabolomics, exome sequencing and phenomics data from the UK Biobank (UKB) to investigate gene-metabolite and metabolite-phenotype relationships. Blood metabolites (N=168) were profiled by Nightingale Health in ~120,000 UKB participants, >90% of whom had exome sequences and all had data on ~16,000 clinical traits.
    We explored genetic associations with blood metabolites by two complementary approaches: (i) single-variant analysis, and (ii) gene-level collapsing analysis, using a linear regression model, adjusted for age, sex and BMI. For the single-variant analysis, we tested ~3.2 million variants under dominant and recessive models. For the gene-level collapsing analysis, the aggregate effect of variants in each gene was tested using 11 different models, including ones that focused on rare (MAF<0.1%) missense and protein-truncating variants. We also performed a metabolite PheWAS, in which the association for each metabolite was tested with each clinical trait.
    Our analyses provide a rich catalogue of significant (p<1x10-8) associations: 10,461 variant-metabolite, 970 gene-metabolite, and 127,947 metabolite-phenotype relationships. This includes well-established, biologically plausible associations such as variants in PAH with phenylalanine levels [beta=1.2; p<1x10-300] and the concentration of intermediate-density lipoprotein particles with type 2 diabetes [beta=-1.5; p<1x10-300]. These data may also provide insights into underlying biological mechanisms: for instance, the observed metabolite signature for mutations in a gene that is a known drug target (e.g, HSD17B13) can indicate the metabolic profile expected with desirable therapeutic response.
    The catalogue of genetic and phenotypic relationships for blood metabolites, which will expand further once metabolomics data becomes available in the entire UKB cohort of ~500,000 subjects, represents an excellent resource to better understand mechanisms underlying complex human diseases. 

    Abhishek Nag
    Centre for Genomics Research, AstraZeneca

    Practical implementation of polygenic risk scores and absolute risk score estimation across diverse ancestry groups

    Polygenic risk scores (PRS) have generated considerable translational interest. Yet, most validation efforts focus on assessing relative rather than absolute risk scores (ARS), even though ARS are required for clinical decision making. ARS validation experiments are typically based on a single large cohort split into training/testing and rarely incorporate PRS. While such approaches typically generate calibrated ARS within the testing dataset, they do not properly capture the complex biases inherent to each healthcare context or account for environmental differences between countries and ethnicities. Consequently, the robustness of the ARS across different contexts is largely unknown.
    To address these gaps, we derived a framework to combine ethnicity-specific disease baselines from a range of country-specific surveys, which capture social determinants of health, with ancestry-adjusted PRS (European OR per 1SD 1.87, 2.10, 1.51 and 2.09 respectively) for breast cancer, prostate cancer (PC), cardiovascular disease (CVD) and type 2 diabetes (T2D). We validated these ARS in independent datasets, computing calibration summary statistics, including the standard incidence ratio (SIR), calibration slope and intercept, and the integrated calibration index.
    We find that inclusion of an ethnic specific baseline captures substantial ARS variability not captured by the PRS, particularly for PC, where an UK African and Caribbean baseline results in calibration (0.99-1.34 95% CI SIR) whilst the UK average baseline results in strong miscalibration (2.24-3.02 95% CI SIR). The extent of the calibration varied, with challenges arising for T2D and CVD, whose incidence has fluctuated across time and location in the US over the last decades. For T2D, baselines date from 1997-2019 but prospective testing data date from 1987-1999, resulting in miscalibration for White males (1.35-1.62 95% CI SIR). For CVD, baselines for myocardial infarction and fatal heart disease date from 2004-2011 and ischemic stroke from 1999, but prospective testing data date from 1986-2000, resulting in miscalibration for White females and males (0.66-0.92 and 1.04-1.31 95% CI SIR respectively).
    We demonstrate that with appropriate data it is possible to translate genetic risk into clinically meaningful ARS that robustly replicate in diverse contexts. Our results also demonstrate the challenges arising from variation across ethnicity, geography and time and the need for population-relevant information on which risk prediction tools are to be applied. 

    Rachel Moore
    Genomics plc

    The Kidney genome atlas reveals a novel locus on chromosome 14 associated with adult proteinuric kidney diseases

    Chronic Kidney disease (CKD) affects 1 in 9 people worldwide. There is a high unmet need for drugs that extend and restore kidney function, because dialysis and organ transplantation carry substantial economic and psychological burden. To foster drug development of genetically validated targets, we have created the Kidney Genome Atlas (KGA) by assembling ~23,000 whole genomes from 2,832 kidney disease cases including proteinuric kidney disease cases such as Focal segmental glomerulosclerosis (571 cases), minimal change disease (244 cases), nephrotic syndrome (196 cases) and idiopathic proteinuria (1,123 cases) and 19,804 controls. Following the gnomAD pipeline, we implemented a rigorous quality control procedure to obtain a high confidence dataset for downstream analyses of proteinuric kidney diseases. Ancestries were inferred genetically based on a k-NN model trained on 1,000 Genomes data which resulted in 597 cases and 10,127 controls of European (EUR) ancestry, 513 cases and 3,805 controls of African (AFR) ancestry, and 290 cases and 754 controls of Latino/Admixed American (AMR) ancestry for association testing. Meta-analysis of common variants across ancestries showed minimal impact of potential confounders, such as ancestry or sequencing center differences (lambda=1.03). We identified a novel locus on chromosome 14 (rs11160484; effect size = -0.42, P = 2.8*10-8) associated with proteinuric kidney disease. In addition, we confirmed the well-known association of APOL1 risk haplotypes (G1/G1, G2/G2 or G1/G2; effect size = 0.50, P = 2.4*10-9, under recessive model) in the AFR cohort. LD-score regression analysis revealed a trend towards a weak positive genetic correlation (rg = 0.097, 90% CI [0.010, 0.18]) between proteinuric kidney diseases and CKD defined by estimated glomerular filtration rate or eGFR (Wuttke et al, 2019). Using summary statistics from our EUR dataset, we estimated the SNP heritability of proteinuric kidney diseases at 0.15 (95% CI [0.095, 0.20]), suggesting that there may be many more genetic contributions that are yet to be discovered. These findings advance our understanding of the genetic architecture of proteinuric kidney diseases and highlight an opportunity for novel therapies and patient stratification. 

    Eva Fast
    Goldfinch Bio

  • Behind-the-Scenes: Publications Workshop
    Contains 1 Component(s)

    Information to help navigate the scientific publication process

    This workshop will provide you with information to help navigate the scientific publication process. Journal editors will give you a behind scenes view of scientific publishing during a moderated panel discussion. There will be plenty of time to ask questions, as well as an opportunity to speak directly with editors from AJHG, HGG Advances, and Cell Genomics. This session is geared towards trainees and junior faculty who are relatively new to publishing. For more information, please view the "Details" tab. 

    Recorded session from the 2021 virtual meeting.

    Behind-the-Scenes: Publications Workshop

    This workshop will provide you with information to help navigate the scientific publication process. Journal editors will give you a behind scenes view of scientific publishing during a moderated panel discussion. There will be plenty of time to ask questions, as well as an opportunity to speak directly with editors from AJHG, HGG Advances, and Cell Genomics. This session is geared towards trainees and junior faculty who are relatively new to publishing.

    Moderator: Sara Cullinan, AJHG

    Speakers: 

    - Jessica Chong, PhD, University of Washington

    - Bruce Korf, MD, PhD, AJHG, University of Alabama at Birmingham

    - Mike Bamshad, MD, University of Washington, HGG Advances 

    - Orli Bahcall, PhD, Cell Genomics

  • How to Land a Postdoctoral Position as a Trainee and Fill a Postdoctoral Position as a Research Advisor
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    A panel discussion on how to find a postdoctoral position after completing graduate school and how to fill a postdoctoral position in your lab as a research advisor.

    This Professional Development Program session will feature a panel discussion on how to find a postdoctoral position after completing graduate school and how to fill a postdoctoral position in your lab as a research advisor. The topics will cover postdoctoral positions in academia and industry. The session will be followed by 20 minutes of Q/A. This panel is organized and moderated by the ASHG Career Development Committee.

    Recorded session from the 2021 virtual meeting.

    Professional Development Program: Tips on How to Land a Postdoctoral Position as a Trainee and Fill a Postdoctoral Position in Your Lab as a Research Advisor

    This Professional Development Program session will feature a panel discussion on how to find a postdoctoral position after completing graduate school and how to fill a postdoctoral position in your lab as a research advisor. The topics will cover postdoctoral positions in academia and industry. The session will be followed by 20 minutes of Q/A. This panel is organized and moderated by the ASHG Career Development Committee.

    Moderator: Ky’Era Actkins, BS, Graduate Student, Meharry Medical College

    Panelists:

    - Andrew Marderstein, PhD, Postdoctoral Fellow, Stanford University

    - Athena Starlard-Davenport, PhD, Associate Professor, University of Tennessee Health Sciences Center

    - Lindsay Stolzenburg, PhD, Scientist at Exicure, Inc.

    - Cristopher Van Hout, PhD, Assistant Professor, National Autonomous University of Mexico

  • Professional Development Program: Industry & Biotechnology Careers Panel
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    A panel discussion on careers in Industry and Biotechnology

    This Professional Development Program session will feature a panel discussion on careers in Industry and Biotechnology along with Q/A from attendees. There will be a special emphasis on how to transition into industry careers. This panel is organized and moderated by the ASHG Career Development Committee.

    Recorded session from the 2021 virtual meeting.

    Professional Development Program: Industry & Biotechnology Careers Panel

    This Professional Development Program session will feature a panel discussion on careers in Industry and Biotechnology along with Q/A from attendees. There will be a special emphasis on how to transition into industry careers. This panel is organized and moderated by the ASHG Career Development Committee.

    Moderator: Danjuma Quarless, PhD, Senior Computational Scientist, Abbvie

    Panelists: 

    - Kate Cunningham, PhD, Sr. Manager for Customer Service and Support, Miroculus 

    - Aaron Friedman, PhD, Principal Startup Solutions Architect, Healthcare & Life Sciences, Amazon Web Services 

    - Josephine Lee, Sr. Director, Molecular Biology, 10X Genomics 

    - Jeffrey Reid, PhD, Vice President, RGC Chief Data Officer, Regeneron

  • ASHG Presidential Address 2021: Imagination and Daring: Past, Present, and Future
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    ASHG President Dr. Gail Jarvik reflects on advances in human genetics and how her own personal journey as a woman in science informs the need for better inclusion in our field and in our society

    ASHG President Dr. Gail Jarvik reflects on advances in human genetics and how her own personal journey as a woman in science informs the need for better inclusion in our field and in our society. She addresses some steps that are needed to achieve ASHG’s stated vision that “people everywhere realize the benefits of human genetics and genomics research.”

    Recorded session from the 2021 virtual meeting.

    ASHG Presidential Address - Imagination and Daring: Past, Present, and Future
    ASHG President Dr. Gail Jarvik will reflect on advances in human genetics and how her own personal journey as a woman in science informs the need for better inclusion in our field and in our society. She addresses some steps that are needed to achieve ASHG’s stated vision that “people everywhere realize the benefits of human genetics and genomics research.”

    Speaker: Gail P Jarvik, MD, PhD