Principles and methods for transferring polygenic risk scores across global populations.

Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.

Improving reporting standards for polygenic scores in risk prediction studies.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.

Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets.

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected because of a lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWASs excludes detection of sites that are in LD but might underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for associations between 23 common diseases and 5,625,845 epistatic SNP-SNP pairs (determined by Ohta's D statistics) in long-range LD (>0.25 cM). Across five disease phenotypes, we identified one significant and four near-significant associations that replicated in two large genotype-phenotype datasets (UK Biobank and eMERGE). The genes that were most likely involved in the replicated associations were (1) members of highly conserved gene families with complex roles in multiple pathways, (2) essential genes, and/or (3) genes that were associated in the literature with complex traits that display variable expressivity. These results support the highly pleiotropic and conserved nature of variants in long-range LD under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and might especially be driving factors in conditions with a wide range of phenotypic outcomes.

Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Deep generative models of LDLR protein structure to predict variant pathogenicity.

The complex structure and function of low density lipoprotein receptor (LDLR) makes classification of protein-coding missense variants challenging. Deep generative models, including Evolutionary model of Variant Effect (EVE), Evolutionary Scale Modeling (ESM), and AlphaFold 2 (AF2), have enabled significant progress in the prediction of protein structure and function. ESM and EVE directly estimate the likelihood of a variant sequence but are purely data-driven and challenging to interpret. AF2 predicts LDLR structures, but variant effects are explicitly modeled by estimating changes in stability. We tested the effectiveness of these models for predicting variant pathogenicity compared to established methods. AF2 produced two distinct conformations based on a novel hinge mechanism. Within ESM's hidden space, benign and pathogenic variants had different distributions. In EVE, these distributions were similar. EVE and ESM were comparable to Polyphen-2, SIFT, REVEL, and Primate AI for predicting binary classifications in ClinVar. However, they were more strongly correlated with experimental measures of LDL uptake. AF2 poorly performed in these tasks. Using the UK Biobank to compare association with clinical phenotypes, ESM and EVE were more strongly associated with serum LDL-C than Polyphen-2. ESM was able to identify variants with more extreme LDL-C levels than EVE and had a significantly stronger association with atherosclerotic cardiovascular disease. In conclusion, AF2 predicted LDLR structures do not accurately model variant pathogenicity. ESM and EVE are competitive with prior scoring methods for prediction based on binary classifications in ClinVar but are superior based on correlations with experimental assays and clinical phenotypes.

Penalized mediation models for multivariate data.

Statistical methods to integrate multiple layers of data, from exposures to intermediate traits to outcome variables, are needed to guide interpretation of complex data sets for which variables are likely contributing in a causal pathway from exposure to outcome. Statistical mediation analysis based on structural equation models provide a general modeling framework, yet they can be difficult to apply to high-dimensional data and they are not automated to select the best fitting model. To overcome these limitations, we developed novel algorithms and software to simultaneously evaluate multiple exposure variables, multiple intermediate traits, and multiple outcome variables. Our penalized mediation models are computationally efficient and simulations demonstrate that they produce reliable results for large data sets. Application of our methods to a study of vascular disease demonstrates their utility to identify novel direct effects of single-nucleotide polymorphisms (SNPs) on coronary heart disease and peripheral artery disease, while disentangling the effects of SNPs on the intermediate risk factors including lipids, cigarette smoking, systolic blood pressure, and type 2 diabetes.

Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study.

BACKGROUND: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. METHODS: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. RESULTS: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. CONCLUSIONS: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier; NCT03394859.

Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups.

Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRSTikkanen and PRSTada; 28 and 50 variants, respectively) and two genome-wide PRSs (PRSmetaGRS and PRSLDPred; 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRSmetaGRS, the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46-1.60), 1.53 (1.23-1.90), and 1.27 (1.13-1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (pinteraction = 0.77) but were significantly attenuated in AA individuals (pinteraction= 2.9 × 10-3). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.

Implementing Reporting Standards for Polygenic Risk Scores for Atherosclerotic Cardiovascular Disease.

PURPOSE OF REVIEW: There is considerable interest in using polygenic risk scores (PRSs) for assessing risk of atherosclerotic cardiovascular disease (ASCVD). A barrier to the clinical use of PRSs is heterogeneity in how PRS studies are reported. In this review, we summarize approaches to establish a uniform reporting framework for PRSs for coronary heart disease (CHD), the most common form of ASCVD. RECENT FINDINGS: Reporting standards for PRSs need to be contextualized for disease specific applications. In addition to metrics of predictive performance, reporting standards for PRSs for CHD should include how cases/control were ascertained, degree of adjustment for conventional CHD risk factors, portability to diverse genetic ancestry groups and admixed individuals, and quality control measures for clinical deployment. Such a framework will enable PRSs to be optimized and benchmarked for clinical use.

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Multiancestral polygenic risk score for pediatric asthma.

BACKGROUND: Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait. OBJECTIVES: This study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries. METHODS: This study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes. RESULTS: The multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, PFDR = 3.71 × 10-65) and related phenotypes. CONCLUSIONS: A multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.

Transgelin: a new gene involved in LDL endocytosis identified by a genome-wide CRISPR-Cas9 screen.

A significant proportion of patients with elevated LDL and a clinical presentation of familial hypercholesterolemia do not carry known genetic mutations associated with hypercholesterolemia, such as defects in the LDL receptor. To identify new genes involved in the cellular uptake of LDL, we developed a novel whole-genome clustered regularly interspaced short palindromic repeat-Cas9 KO screen in HepG2 cells. We identified transgelin (TAGLN), an actin-binding protein, as a potentially new gene involved in LDL endocytosis. In silico validation demonstrated that genetically predicted differences in expression of TAGLN in human populations were significantly associated with elevated plasma lipids (triglycerides, total cholesterol, and LDL-C) in the Global Lipids Genetics Consortium and lipid-related phenotypes in the UK Biobank. In biochemical studies, TAGLN-KO HepG2 cells showed a reduction in cellular LDL uptake, as measured by flow cytometry. In confocal microscopy imaging, TAGLN-KO cells had disrupted actin filaments as well as an accumulation of LDL receptor on their surface because of decreased receptor internalization. Furthermore, TAGLN-KO cells exhibited a reduction in total and free cholesterol content, activation of SREBP2, and a compensatory increase in cholesterol biosynthesis. TAGLN deficiency also disrupted the uptake of VLDL and transferrin, other known cargoes for receptors that depend upon clathrin-mediated endocytosis. Our data suggest that TAGLN is a novel factor involved in the actin-dependent phase of clathrin-mediated endocytosis of LDL. The identification of novel genes involved in the endocytic uptake of LDL may improve the diagnosis of hypercholesterolemia and provide future therapeutic targets for the prevention of cardiovascular disease.

Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10-8 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10-8 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10-5 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

Uterine fibroid polygenic risk score (PRS) associates and predicts risk for uterine fibroid.

Uterine fibroids (UF) are common pelvic tumors in women, heritable, and genome-wide association studies (GWAS) have identified ~ 30 loci associated with increased risk in UF. Using summary statistics from a previously published UF GWAS performed in a non-Hispanic European Ancestry (NHW) female subset from the Electronic Medical Records and Genomics (eMERGE) Network, we constructed a polygenic risk score (PRS) for UF. UF-PRS was developed using PRSice and optimized in the separate clinical population of BioVU. PRS was validated using parallel methods of 10-fold cross-validation logistic regression and phenome-wide association study (PheWAS) in a seperate subset of eMERGE NHW females (validation set), excluding samples used in GWAS. PRSice determined pt < 0.001 and after linkage disequilibrium pruning (r2 < 0.2), 4458 variants were in the PRS which was significant (pseudo-R2 = 0.0018, p = 0.041). 10-fold cross-validation logistic regression modeling of validation set revealed the model had an area under the curve (AUC) value of 0.60 (95% confidence interval [CI] 0.58-0.62) when plotted in a receiver operator curve (ROC). PheWAS identified six phecodes associated with the PRS with the most significant phenotypes being 218 'benign neoplasm of uterus' and 218.1 'uterine leiomyoma' (p = 1.94 × 10-23, OR 1.31 [95% CI 1.26-1.37] and p = 3.50 × 10-23, OR 1.32 [95% CI 1.26-1.37]). We have developed and validated the first PRS for UF. We find our PRS has predictive ability for UF and captures genetic architecture of increased risk for UF that can be used in further studies.

A pragmatic clinical trial of cascade testing for familial hypercholesterolemia.

PURPOSE: We compared new cases detected per index case in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology. METHODS: We enrolled 52 FH probands with a pathogenic variant (FHg+) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FHg-). After direct contact by the study team, family members (FMs) of FHg+ probands could opt-in for genetic testing and FMs of FHg- probands were asked to provide a lipid profile. New cases were defined as presence of a pathogenic variant in FHg+ families and as low-density lipoprotein cholesterol ≥155 mg/dL in FHg- families. RESULTS: Of 71 FHg+ probands seen by a genetic counselor, 52 consented and identified 253 FMs (111 consented and were tested, yielding 48 new cases). Of 101 FHg- probands who received counseling, 73 consented and identified 295 FMs (63 consented and were tested, yielding 17 new cases). New case detection per index case was significantly greater in FHg+ than in FHg- families (0.92 vs 0.23), a result of higher cascade testing uptake (43.9 vs 21.4%) and yield (43.2 vs 27.0%) in the former. CONCLUSION: New case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.

Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results.

PURPOSE: We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results. METHODS: Participants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits. Outcomes occurring within 1 year of return of results included new diagnoses, referral to a specialist, new tests ordered, surveillance initiated, and new medications started. RESULTS: P/LP variants were present in 34 participants. The average penetrance across genes was 59%, ranging from 86% for FBN1 variants to 25% for SMAD3. Of 16 participants in whom results were returned, 1-year outcomes occurred in 63%. A new diagnosis was made in 44% of the participants, 56% were referred to a specialist, a new test was ordered in 44%, surveillance was initiated in 31%, and a new medication was started in 31%. CONCLUSION: Penetrance of P/LP variants in arteriopathy-related genes, identified in a large, targeted sequencing study, was variable and overall lower than that reported in clinical cohorts. Meaningful outcomes within the first year were noted in 63% of participants who received results.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

Do research participants share genomic screening results with family members?

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.