Citations

Background: Enthusiasm for using polygenic risk scores (PRSs) in clinical practice is tempered by concerns about their portability to diverse ancestry groups, thus motivating genome-wide association studies in non-European ancestry cohorts. Methods: We conducted a genome-wide association study for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 PRSs developed with methods including LDpred (PGS000296), metaGRS (PGS000018), Pruning and Thresholding (PGS000337), and an EnsemblePRS we developed. Additionally, we evaluated the burden of rare variants in lipid genes in cases and controls. Whole genome sequencing at 30× coverage was performed in 1067 coronary heart disease cases (mean age=59 years; 70.3% males) and 6170 controls (mean age=40 years; 43.5% males). Results: The majority of PRSs performed well; odds ratio (OR) per 1 SD increase (OR 1sd ) was highest for PGS000337 (OR 1sd =1.81, 95% CI [1.66–1.98], P =3.07×10 −41 ). EnsemblePRS performed better than individual PRSs (OR 1sd =1.8, 95% CI [1.66–1.96], P =5.89×10 −44 ). The OR for the 10th decile versus the remaining deciles was >3.2 for PGS000337, PGS000296, PGS000018, and reached 4.58 for EnsemblePRS. Of 400 known genome-wide significant loci, 33 replicated at P <10 −4 . However, the 9p21 locus did not replicate. Six suggestive ( P <10 −5 ) new loci/genes with plausible biological function were identified (eg, CORO7 , RBM47 , PDE4D ). The burden of rare functional variants in LDLR , APOB , PCSK9 , and ANGPTL4 was greater in cases than controls. Conclusions: Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed.

Introduction: We aimed to identify and characterize carotid artery stenosis (CAS), defined as ≥40% stenosis in the internal carotid artery (ICA) or the common carotid artery (CCA), among participants of the Mayo Vascular Disease Biorepository (VDB, n = 11,814). Hypothesis: A string-based text processing (TP) tool coded in R can analyze radiology text reports to ascertain and characterize CAS. Methods: After importing a radiology report into R, it was segmented for analysis and each segment was tested for 22 unique features. The TP tool was able to i) identify stenosis in the ICA or the CCA while excluding stenosis of vertebral arteries, subclavian arteries, or external carotid arteries, ii) recognize both quantitative and qualitative descriptions of CAS, iii) interpret numerical expressions by considering the surrounding text, iv) detect negations, and v) ascertain previous revascularization procedures if mentioned in the text. We manually ascertained CAS and characterized it in 800 randomly selected radiology reports to assess the performance of the TP tool in terms of precision, recall, and F-score. Results: We retrieved 21,651 imaging reports for 6,342 unique patients including 20,461 ultrasonography reports, 812 magnetic resonance imaging reports, 357 computed tomography scan reports, and 21interventional radiology reports. The performance of TP is outlined in Table 1 . Conclusion: We demonstrate that a string-based TP tool coded in R is efficient and accurate in identifying and characterizing CAS from carotid radiology reports. The tool does not require natural language processing and could be used in a wide range of settings for genetic and biomarker studies.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) refers to the formation of genetically distinct subpopulations of blood cells due to somatic mutations. CHIP is associated with a variety of adverse outcomes, including hematological cancers, cardiovascular disease, and death. We sought to investigate the association of CHIP with incident venous thromboembolism (VTE). Methods: We analyzed exome sequence data from 200,628 individuals in the UK Biobank cohort using Mutect2 to identify a prespecified list of somatic mutations in DNMT3A, TET2, and ASXL1, which are known genetic drivers of CHIP. CHIP was defined as harboring a somatic mutation at a variant allele fraction (VAF) ≥10% and individuals with VAF <2% were deemed as non-carriers. VTE was ascertained using verbal interview data and diagnostic/procedural codes and defined as a composite of the following: thrombophlebitis of deep veins of lower limbs, embolism/thrombosis of vena cava, pulmonary embolism, venous thrombectomy of lower limb veins or IVC filter insertion. We implemented a nested case-control design with incidence density sampling to identify incident cases and controls matched (1:8 ratio) for sex, smoking status, and history of malignancy at baseline. Conditional logistic regression analysis adjusted for age, BMI, and genetic ancestry was performed to assess the association between CHIP and incident VTE. Results: Among 200,628 individuals, we identified 3,885 individuals with CHIP at baseline and 748 incident VTE events during a median follow-up of 9.2 years. In 748 incident cases and 5984 matched controls, CHIP was associated with increased risk of incident VTE independent of conventional risk factors for VTE, namely, age, sex, BMI, smoking, and history of malignancy (incidence rate ratio [95% confidence interval]; 1.60 [1.04-2.46], p=0.032). When we restricted the cases to individuals with incident pulmonary embolism (n=441), we observed a stronger association with CHIP (1.80 [1.08-3.05], p=0.025). Conclusions: CHIP is associated with increased risk of VTE independent of history of malignancy and other conventional risk factors. The pathophysiological basis for this association needs further investigation.

Introduction: The prevalence of atrial fibrillation (AF) increases with age and inflammation plays a key pathophysiologic role. Somatic mosaicism increases with age and promotes inflammation. Therefore, we investigated whether Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a risk factor for incident AF. Methods: We assessed exome sequence (ES) data from 200,628 participants in the UK biobank. Using the Genome Analysis Toolkit pipeline, we ascertained a predefined list of CHIP mutations in DNMT3A , TET2 , and ASXL1 . CHIP was defined as variant allele frequency (VAF) >10% and those with VAF <2% served as controls. AF was ascertained based on self-report and ICD codes. Lone AF was defined as AF in the absence of heart failure, mitral stenosis, mitral valve repair/valvotomy/replacement, and congenital heart disease. Those with AF prior to or at the time of enrollment were excluded from analyses to ascertain incident events. Cox proportional hazard models adjusted for age, sex, self-reported race/ethnicity, diabetes, hypertension, smoking, and obesity were used to identify associations between CHIP and incident AF. Results: Of 200,628 participants, 3885 (1.9%) had CHIP. The number of participants with mutations in DNMT3A , TET2 , and ASXL1 was 2512, 1065, and 439, respectively. During a median follow-up of 9 years, 4,676 incident AF and 3,584 incident lone AF occurred. CHIP was an independent risk factor for developing incident AF and also for developing lone AF. CHIP in TET2 and ASXL1 but not DNMT3A was associated with AF ( Table 1 ). Conclusions: The presence of CHIP involving TET2 and ASXL1 is associated with an increased risk of incident AF including the subset with lone AF. Our findings reveal somatic mosaicism in blood cells to be a novel risk factor for AF.

Introduction: The potential use of polygenic risk scores (PRSs) in clinical practice is tempered by concern about their portability among diverse populations. To prevent disparities in genomic medicine, there is an urgent need to conduct genome-wide association studies in non-European ancestry cohorts. Methods: We conducted whole genome sequencing (WGS) with 30x coverage on coronary heart disease patients (n=1,067, mean age ± SD = 59.96 years ± 10.99; 70.32% males) and controls (n=6,170, mean age ± SD = 40.02 years ± 12.56; 43.45% males) in a Middle Eastern cohort to compare the performance of available PRSs for CHD (LDpred, metaGRS, lassosum, and P+T) and identify common variants associated with CHD (via generalized linear mixed models). Results: Excepting lassosum, all PRSs performed well. LDpred and metaGRS performed similarly (AUC= ~0.685) and outperformed P+T (AUC=0.667). Based on the OR per 1 SD increase (OR 1sd ), P+T (OR 1sd =1.85 [1.69-2.02], P =3.69x10 -41 ) outperformed other PRSs (OR 1sd =1.61 [1.48-1.74], P =3.02x10 -31 for LDpred and OR 1sd =1.61 [1.49-1.75], P =9.47x10 -31 for metaGRS). After binning PRSs into 10 deciles, the odds of CHD in the top decile compared to all others was highest for metaGRS (3.87 [3.07-4.88]) and LDpred (3.45 [2.74-4.341]). Thirty-two known GWAS loci (e.g., ABCG8 , CELSR2 , and SLC22A4 ) were replicated in our analysis with P <0.05. Seven suggestive new loci/genes ( P <10 -6 ) with relevant biological function were identified (e.g., CORO7 , RBM47 , and PDE4D ). The well-established 9p21 locus was not replicated. Conclusions: Genome-wide PRSs derived from European ancestry cohorts performed well in a Middle Eastern cohort. Further studies are needed to develop and validate an ancestry specific PRS and to confirm the suggestive loci/genes.

The Clinical Genome Resource Consortium (ClinGen) recommends MaxEntScan (MES) model to predict effects of LDLR splice variants. We developed “MaxSpliZer”, a software tool to automate implementation of MES and validated it using ClinVar and UK-Biobank (UKBB) data. We tested concordance of MaxSpliZer predictions with ClinVar classifications of pathogenicity of variants in LDLR and FBN1 with potential effect on splicing. We also annotated LDLR splice variants in 200,618 UKBB participants, categorizing them using MaxSpliZer as deleterious (n=90) and non-deleterious (n=7,404). Low-density lipoprotein cholesterol (LDL-C) levels were compared in these two groups after adjustment for lipid lowering medication use. MaxSpliZer prediction was concordant with the ClinVar classification in 96% of LDLR variants and 98% of FBN1 variants. In the UKBB, splice variants predicted as deleterious by MaxSpliZer had higher LDL-C than non-deleterious splice variants (158.7±47.4 vs. 146.0±34.8mg/dL, p-value = 0.014). Compared to manual curation time of 12±7 min per variant, MaxSpliZer took 0.52±0.11 min for single entries and 1.5 s per variant for biobank-scale data. MaxSpliZer, a software tool that implements MES based on the ClinGen guideline, can accurately classify splice variants in a rapid automated fashion.

The Clinical Genome Resource Consortium (ClinGen) recommends MaxEntScan (MES) model to predict effects of LDLR splice variants. We developed “MaxSpliZer”, a software tool to automate implementation of MES and validated it using ClinVar and UK-Biobank (UKBB) data. We tested concordance of MaxSpliZer predictions with ClinVar classifications of benign/likely benign (B/LB) and pathogenic/likely pathogenic (P/LP) for LDLR variants with potential effect on splicing. We also annotated LDLR splice variants in 200,618 UKBB participants, categorizing them using MaxSpliZer as deleterious (n=90) and non-deleterious (n=7,404). Low-density lipoprotein cholesterol (LDL-C) levels were compared in these two groups after adjustment for lipid lowering medication use. MaxSpliZer prediction was concordant with the ClinVar classification in 128 of 138 P/LP variants (sensitivity 93%) and 432 of 436 B/LB variants (specificity 99%). In the UKBB, splice variants predicted as deleterious by MaxSpliZer had higher LDL-C than non-deleterious splice variants (158.7±47.4 vs. 146.0±34.8mg/dL, p-value = 0.014). Compared to manual curation time of 12±7 min per variant, MaxSpliZer took 0.52±0.11 min for single entries and 1.5 s per variant for biobank-scale data. MaxSpliZer, a software tool that implements MES based on the ClinGen guideline, can accurately classify LDLR splice variants in a rapid automated fashion.

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.

Abstract BACKGROUND The purpose of this document is to provide clinicians with guidance, using expert consensus, to help summarize evidence and offer practical recommendations. METHODS Expert Consensus Documents are intended to provide guidance for clinicians in areas in which there are no clinical practice guidelines, especially for new and evolving tests such as arterial stiffness measurements, until any formal guidelines are released. RESULTS This expert consensus document is intended as a source of information for decision-making and to guide clinician–patient discussions in various clinical scenarios. CONCLUSIONS The goal is to help clinicians and patients make a more informed decision together.