Penn Medicine Biobank Research Articles

Evaluating Performance and Agreement of Coronary Heart Disease Polygenic Risk Scores.

Polygenic risk scores (PRSs) for coronary heart disease (CHD) are a growing clinical and commercial reality. Whether existing scores provide similar individual-level assessments of disease susceptibility remains incompletely characterized. To characterize the individual-level agreement of CHD PRSs that perform similarly at the population level. Cross-sectional study of participants from diverse backgrounds enrolled in the All of Us Research Program (AOU), Penn Medicine BioBank (PMBB), and University of California, Los Angeles (UCLA) ATLAS Precision Health Biobank with electronic health record and genotyping data. Polygenic risk for CHD from published PRSs and new PRSs developed separately from testing samples. PRSs that performed population-level prediction similarly were identified by comparing calibration and discrimination of models of prevalent CHD. Individual-level agreement was tested with intraclass correlation coefficient (ICC) and Light κ. A total of 48 PRSs were calculated for 171 095 AOU participants. The mean (SD) age was 56.4 (16.8) years. A total of 104 947 participants (61.3%) were female. A total of 35 590 participants (20.8%) were most genetically similar to an African reference population, 29 801 (17.4%) to an admixed American reference population, 100 493 (58.7%) to a European reference population, and the remaining to Central/South Asian, East Asian, and Middle Eastern reference populations. There were 17 589 participants (10.3%) with and 153 506 participants without (89.7%) CHD. When included in a model of prevalent CHD, 46 scores had practically equivalent Brier scores and area under the receiver operator curves (region of practical equivalence ±0.02). Twenty percent of participants had at least 1 score in both the top and bottom 5% of risk. Continuous agreement of individual predictions was poor (ICC, 0.373 [95% CI, 0.372-0.375]). Light κ, used to evaluate consistency of risk assignment, did not exceed 0.56. Analysis among 41 193 PMBB and 53 092 ATLAS participants yielded different sets of equivalent scores, which also lacked individual-level agreement. CHD PRSs that performed similarly at the population level demonstrated highly variable individual-level estimates of risk. Recognizing that CHD PRSs may generate incongruent individual-level risk estimates, effective clinical implementation will require refined statistical methods to quantify uncertainty and new strategies to communicate this uncertainty to patients and clinicians.

Estimated clinical utility of multi-gene pharmacogenetic testing in a retrospective cohort of gynecology patients.

This study aimed to estimate the clinical utility of performing multi-gene pharmacogenetic testing on patients undergoing gynecologic surgery/procedure by evaluating the prescribing rate of Clinical Pharmacogenetics Implementation Consortium (CPIC) level A medications and frequency of drug-gene interactions (DGIs). The electronic health record was queried for 76 current procedural terminology codes to identify gynecologic surgeries/procedures that occurred between 1 January 2015 to 31 December 2020 in patients with at least one of 152 international classification of disease codes. Prescription data for CPIC level A medications was extracted. Those enrolled in the Penn Medicine Biobank were assessed for DGIs. The cohort consisted of 7798 female patients and 682 were in the biobank. Up to 6 years following their surgery or procedure, 80% were ordered ≥1 CPIC level A medication. Over half (54%) of these medications were ordered within 3 days after their surgery or procedure. The most common CPIC level A medications ordered were ibuprofen (57%) and ondansetron (42%). Overall, 7% of the cohort had ≥1 known or predicted DGI with medications they were prescribed. Multi-gene pharmacogenetic testing may be beneficial to gynecologic surgery/procedure patients by assisting clinicians with prescribing postoperative analgesics and future medications.

Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3.

The genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM. To interrogate the clinical traits and diseases associated with BAG3 coding variation. This was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System's clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study. Carrier status for BAG3 coding variants. Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. In PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358). BAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

Abstract 4138455: Employing Bioinformatic Tools to Identify High-Risk Variants of Unknown Significance in Aortopathy Genes Associated with Aortic Dissection

Introduction: Pathogenic (P) or likely pathogenic (LP) aortopathy gene variants cause hereditary thoracic aortic aneurysm and dissection, but P/LP variants only explain approximately 20% of cases of thoracic aortic disease. Variants of unknown significance (VUS) are frequently identified among individuals undergoing genetic testing for thoracic aortic disease, however managing patients with VUSs remains clinically challenging. Hypothesis: Bioinformatic tools can be used to determine thresholds above which VUSs may be considered “high-risk.” Methods: Primary analyses were performed in the Penn Medicine Biobank (PMBB) which is composed of 43,731 participants who volunteered to have clinical information linked to biospecimen data including DNA which has undergone whole exome sequencing. PMBB participants were screened for VUSs in one of 11 aortopathy genes. VUS REVEL, AlphaMissense and minor allele frequency (MAF) high-risk thresholds were derived using cutpointR, a statistical package to optimize continuous variable thresholds based on binary outcomes. These thresholds were applied to VUS carriers in the PMBB and two independent validation cohorts. Logistic regression analysis was performed to test the association of high-risk VUSs with prevalent thoracic aortic disease. Results: There were 11,925 individuals in PMBB who carried at least one missense VUS. Carrying a VUS was associated with a modest increased risk of thoracic aortic aneurysm (TAA: OR=1.14, 95% confidence interval [CI] 1.01 to 1.29, P =0.034) but no increased risk of thoracic aortic dissection (OR=1.04, 95%CI 0.55 to 2.00, P =0.896). As VUS REVEL or AlphaMissense increased, or MAF decreased, the association between VUSs and thoracic aortic disease became statistically significant. Using cutpointR, we derived REVEL (>0.649), AlphaMissense (>0.2543), and MAF (<8.16x10 -6 ) thresholds that together identified 435 high-risk VUSs robustly associated with prevalent dissection (OR=7.85, 95%CI 4.73 to 13.03, P <0.001), though the association with TAA was attenuated (OR=2.35, 95%CI 1.62 to 3.42, P <0.001). Similar results were observed in the UK Biobank (UKB) and Early Onset Sporadic Thoracic Aortic Dissection (ESTAD) cohorts. Conclusions: VUSs that met high-risk bioinformatic thresholds were strongly associated with prevalent aortic dissection in the PMBB, UKB and ESTAD. Future investigation is warranted to determine if these thresholds can instruct clinical care of individuals carrying aortopathy gene VUSs.

Abstract 4135624: A Hypertrophic Cardiomyopathy Polygenic Score Modifies Penetrance of Pathogenic Hypertrophic and Dilated Cardiomyopathy Variants in Opposite Directions

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathy have been postulated to represent morphologically opposing cardiac disease traits, with genetic pathways implicated in HCM demonstrating inverse relationships with DCM. The degree to which polygenic risk for HCM protects from DCM in individuals at genetic risk of DCM remains unexplored. Research Question: Is polygenic risk for HCM protective against developing DCM in carriers of titin truncating variants? Methods: Associations between polygenic risk for HCM, monogenic variants, and cardiomyopathy outcomes were modeled among Penn Medicine BioBank (PMBB) participants genetically similar to European reference populations using logistic regression. Polygenic risk for HCM was determined using a previously published HCM polygenic score (PGS; PGS Catalog PGS000739; Harper et al. 2021); scores were PCA adjusted, and the mean and variance were normalized using pgsc_calc. Pathogenic variants in definitive HCM genes were identified using ACMG criteria. Titin truncating variants in high percentage spliced in exons (TTNtv) were considered pathogenic. HCM and DCM outcomes were assigned based on diagnosis codes +/- clinical notes in the electronic health record. Results: Of 26,728 PMBB participants, 205 (0.77%) had HCM and 589 (2.2%) had DCM. 289 had a TTNtv, and 144 had a pathogenic HCM variant. Pathogenic HCM variant status (n=144) conferred a 76-fold increase in HCM risk (p=1.8 e-87). A one standard deviation change in HCM PGS had a significant positive association with HCM (OR 1.6; p=1.5e-9) and negative association with DCM (OR 0.72; p=1.e-12). TTNtv status (n=289) was associated with an increased risk of DCM (OR 5.0; p=1.4e-12). An interaction term between TTNtv status and HCM PGS had a negative association with DCM (OR 0.61; p=4.5e-2). Among the top HCM PGS quintile, there was no statistically significant difference in DCM risk between those with and without TTNtv (Figure 1). Conclusions: These results provide additional evidence that HCM and DCM are influenced by polygenic background. We observe that polygenic risk of HCM additively increases risk of HCM among pathogenic HCM variant carriers and may synergistically protect from DCM among TTNtv carriers.

Thoracic Aortic Three-Dimensional Geometry.

Aortic structure impacts cardiovascular health through multiple mechanisms. Aortic structural degeneration occurs with aging, increasing left ventricular afterload and promoting increased arterial pulsatility and target organ damage. Despite the impact of aortic structure on cardiovascular health, three-dimensional (3D) aortic geometry has not been comprehensively characterized in large populations. We segmented the complete thoracic aorta using a deep learning architecture and used morphological image operations to extract multiple aortic geometric phenotypes (AGPs, including diameter, length, curvature, and tortuosity) across various subsegments of the thoracic aorta. We deployed our segmentation approach on imaging scans from 54,241 participants in the UK Biobank and 8,456 participants in the Penn Medicine Biobank. Our method provides a fully automated approach towards quantifying the three-dimensional structural parameters of the aorta. This approach expands the available phenotypes in two large representative biobanks and will allow large-scale studies to elucidate the biology and clinical consequences of aortic degeneration related to aging and disease states.

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum.

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, which affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (P-value < 5×10 -8 ). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes ( MYBPC3 , BAG3 ) and in regulators of lipoprotein ( LPL ) and glucose metabolism ( GIPR , GLP1R ). These signals are enriched in myocyte and adipocyte cell types and can be clustered into 5 broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity, and arrhythmias. Gene burden studies across three biobanks (PMBB, UKB, AOU), including 27,208 individuals with HF and 349,126 without, uncover exome-wide significant (P-value < 1.57×10 -6 ) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN , MYBPC3 , FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common variant heritability (4.3%, 95% CI 3.9-4.7%) is more diffusely spread throughout the genome. Finally, we show that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. Together, these findings provide a genetic link between dysregulated metabolism and HF, and suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

Population Performance and Individual Agreement of Coronary Artery Disease Polygenic Risk Scores.

Polygenic risk scores (PRSs) for coronary artery disease (CAD) are a growing clinical and commercial reality. Whether existing scores provide similar individual-level assessments of disease liability is a critical consideration for clinical implementation that remains uncharacterized. Characterize the reliability of CAD PRSs that perform equivalently at the population level at predicting individual-level risk. Cross-sectional Study. All of Us Research Program (AOU), Penn Medicine Biobank (PMBB), and UCLA ATLAS Precision Health Biobank. Volunteers of diverse genetic backgrounds enrolled in AOU, PMBB, and UCLA with available electronic health record and genotyping data. Polygenic risk for CAD from previously published PRSs and new PRSs developed separately from the testing cohorts. Sets of CAD PRSs that perform population prediction equivalently were identified by comparing calibration and discrimination (Brier score and AUROC) of generalized linear models of prevalent CAD using Bayesian analysis of variance. Among equivalently performing scores, individual-level agreement between risk estimates was tested with intraclass correlation (ICC) and Light's Kappa, measures of inter-rater reliability. 50 PRSs were calculated for 171,095 AOU participants. When included in a model of prevalent CAD, 48 scores had practically equivalent Brier scores and AUROCs (region of practical equivalence = 0.02). Across these scores, 84% of participants had at least one score in both the top and bottom risk quintile. Continuous agreement of individual risk predictions from the 48 scores was poor, with an ICC of 0.351 (95% CI; 0.349, 0.352). Agreement between two statistically equivalent scores was moderate, with an ICC of 0.649 (95% CI; 0.646, 0.652). Light's Kappa, used to evaluate consistency of assignment to high-risk thresholds, did not exceed 0.56 (interpreted as 'fair') across statistically and practically equivalent scores. Repeating the analysis among 41,193 PMBB and 50,748 UCLA participants yielded different sets of statistically and practically equivalent scores which also lacked strong individual agreement. Across three diverse biobanks, CAD PRSs that performed equivalently at the population level produced unreliable individual risk estimates. Approaches to clinical implementation of CAD PRSs must consider the potential for discordant individual risk estimates from otherwise indistinguishable scores.

Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach

Background & AimAn unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. TM6SF2 represents a good candidate for this approach due to its known association with steatotic liver disease (SLD). MethodsWe screened participants with whole-exome sequences in the Penn Medicine Biobank (N>40,000) and the UK Biobank (UKB, N>200,000) for protein-altering variants in TM6SF2 and evaluated their association with liver phenotypes and clinical outcomes. ResultsThree missense variants in TM6SF2 (E167K, L156P, P216L) were associated with an increased risk of clinically-diagnosed and imaging-proven steatosis, independent of PNPLA3 I48M risk allele and hepatitis B/C (p<0.001). E167K homozygotes had significantly increased risk of SLD (OR:5.38, p<0.001), steatohepatitis (OR:5.76, p<0.05) and hepatocellular carcinoma (OR:11.22, p<0.0001) whilst nominal risk of steatohepatitis were present in L156P (OR:2.3, p<0.001) and P216L (OR:4.5, p<0.05) heterozygotes. In addition, carriers of E167K are at a 3-folded increase of at-risk MASH (OR:2.75, p<0.001). CT-derived liver fat scores were higher in E167K and L156P in an allele-dose manner (p<0.05). This corresponded with the UKB nuclear magnetic resonance-derived lipidomic analyses (N=105,348), revealing all carriers to exhibit lower total cholesterol, triglycerides and total choline. In silico predictions suggested that these missense variants cause structural disruptions in the EXPERA domain, leading to reduced protein function. This hypothesis was strengthened with a gene-burden of rare loss-of-function variants in TM6SF2 demonstrating an increased risk of SLD (OR:4.9, p<0.05), primarily driven by a novel rare stop-gain variant (W35X) in the same directionality. ConclusionThe functional genetic study of protein-altering variants provides insights on the association between loss of TM6SF2 function and steatotic liver disease and poses the bases for future mechanistic studies. Impact and implicationsThe genome-first approach expands insights into genetic risk factors for steatotic liver disease with TM6SF2 being a focal point due to its known association with plasma lipid traits. Our findings validated two missense variants (E167K and L156P) to be associated with increased risk of hepatic steatosis on CT and MRI scans, as well as the risk of clinically diagnosed hepatocellular carcinoma independent of the common PNPLA3 I48M risk variant. Notably, we also identified a predicted deleterious missense variant P216L to drive steatotic risk and demonstrated that an aggregated gene burden of rare variants demonstrating complete loss-of-function to be linked to the risk of hepatic steatosis. Combined, this study sets the stage for future mechanistic investigations into the functional consequences of TM6SF2 variants in metabolic dysfunction-associated steatotic liver disease to determine future therapeutic targets.

Facilitating return of actionable genetic research results from a biobank repository: Participant uptake and utilization of digital interventions

Research participants report interest in receiving genetic research results. How best to return results remains unclear. In this randomized pilot study, we sought to assess the feasibility of returning actionable research results through a two-step process including a patient-centered digital intervention as compared to a genetic counselor (GC) in the Penn Medicine biobank. In Step 1, participants with an actionable result and procedural controls (no actionable result) were invited to digital pre-disclosure education and provided options for opting out of results. In Step 2, those with actionable results who had not opted out were randomized to receive results via a digital disclosure intervention or with a GC. Five participants (2%) opted out of results after Step 1. After both steps, 52/113 (46.0%) of eligible cases received results, 5 (4.4%) actively declined results, 34 (30.1%) passively declined and 22 (19.5%) could not be reached. Receiving results was associated with younger age (p<0.001), completing pre-disclosure education (p<0.001) and being in the GC arm (p=0.06). Being older, female, and of Black race were associated with being unable to reach. Older age and Black race were associated with passively declining. 47% of those who received results did not have personal or family history to suggest the mutation, and 55.1% completed clinical confirmation testing. The use of digital tools may be acceptable to participants and could reduce costs of returning results. Low uptake, disparities in uptake, and barriers to confirmation testing will be important to address to realize the benefit of returning actionable research results.

Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles.

BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of 6 APOL genes that have arisen as a result of gene duplication.METHODSUsing a genome-first approach in the Penn Medicine BioBank, we identified 62 protein-altering variants in the 6 APOL genes with a minor allele frequency of >0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies.RESULTSWe identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD, including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease.CONCLUSIONThis study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships.FUNDINGNational Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), and National Center for Advancing Translational Sciences (UL1-TR-001878).

Genetic predictors of blood pressure traits are associated with preeclampsia

Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University’s BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (ORDBP = 1.10, 95% CI 1.02–1.17, p = 7.68 × 10−3; ORSBP = 1.16, 95% CI 1.09–1.23, p = 2.23 × 10−6; ORPP = 1.14, 95% CI 1.07–1.27, p = 9.86 × 10−5). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.

Targeted Quantitative Plasma Metabolomics Identifies Metabolite Signatures that Distinguish Heart Failure with Reduced and Preserved Ejection Fraction.

Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop HF disease phenotype-specific approaches to define and guide treatment, distinguishing biomarkers are needed. The goal of this study was to utilize quantitative metabolomics on a large, diverse population to replicate and extend existing knowledge of the plasma metabolic signatures in human HF. Quantitative, targeted LC/MS plasma metabolomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). A total of 90 metabolites were analyzed, comprising 28 amino acids, 8 organic acids, and 54 acylcarnitines. 733 of these samples were also processed via an OLINK protein panel for proteomic profiling. Consistent with previous studies, unsaturated forms of medium/long chain acylcarnitines were elevated in the HFrEF group to a greater extent than the HFpEF group compared to Controls. A number of amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline, and symmetric (SDMA) and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. Plasma branched-chain amino acids (BCAA) were not different across the groups; however, short-chain acylcarnitine species indicative of BCAA catabolism were significantly elevated in both HF groups. The ketone body 3-hydroxybutyrate (3-HBA) and its metabolite C4-OH carnitine were uniquely elevated in the HFrEF group. Linear regression models demonstrated a significant correlation between plasma 3-HBA and NT-proBNP in both forms of HF, stronger in HFrEF. These results identify plasma signatures that are shared as well as potentially distinguish between HFrEF and HFpEF. Metabolite markers for ketogenic metabolic reprogramming in extra-cardiac tissues were identified as unique signatures in the HFrEF group, possibly related to the lipolytic action of increased levels of BNP. Future studies will be necessary to further validate these metabolites as HF biosignatures that may guide phenotype-specific therapeutics and provide insight into the systemic metabolic responses to HFpEF and HFrEF.

Genome-Wide Association Study Identifies Genes for Hair Growth and Patterning are Associated With Pilonidal Disease.

Pilonidal sinus disease is a highly morbid condition characterized by the formation of chronic sinus tracts throughout the sacrococcygeal region. Despite its commonality and strong association with family history, no prior investigation of genetic risk factors for pilonidal sinus disease exists. To identify genetic risk factors for pilonidal sinus disease. A genome-wide association study. The United Kingdom Biobank, FinnGen Biobank, and Penn Medicine BioBank. There were 772,072 participants. Genome-wide significant variants ( p < 5 × 10 -8 ) were mapped to genes using physical distance and gene expression in skin. Genetic correlation between pilonidal sinus disease and morphometric, androgen-driven, and hair phenotypes was estimated with linkage disequilibrium score regression. Finally, a genome-first approach to rare predicted deleterious variants in hair shaft genes TCHH , PADI3 , and TGM3 was conducted for association with pilonidal sinus disease via the Penn Medicine BioBank. A genome-wide association study comprising 2835 individuals with pilonidal sinus disease identified 5 genome-wide significant loci, prioritizing HDAC9, TBX15, WARS2, RP11-293M10.1 , PRKAR1B , TWIST1, GPATCH2L, NEK9 , and EIF2B2 , as putative causal genes; several of these genes have known roles in balding and hair patterning. There was a significant correlation between the genetic background of pilonidal sinus disease and the androgen-driven hair traits of male pattern baldness and young age at first facial hair. In a candidate analysis of genes associated with syndromic hair disorders, rare coding variants in TCHH , a monogenic cause of uncombable hair syndrome, were associated with increased prevalence of pilonidal sinus disease (OR 4.81 [95% CI, 2.06-11.2]). This study is limited to European ancestry. However, because there is a higher incidence of pilonidal sinus disease in men of European ancestry, this analysis is focused on the at-risk population. Genetic analysis of pilonidal sinus disease identified shared genetic architecture with hair biology and androgen-driven traits. As the first study investigating the genetic basis of pilonidal sinus disease, this provides biological insight into the long-appreciated connection between the disease state, male sex, and hair. See Video abstract. ANTECEDENTES:La enfermedad del seno pilonidal es una condición muy mórbida caracterizada por la formación de tractos sinusales crónicos en toda la región sacrococcígea. A pesar de su frecuencia y su fuerte asociación con los antecedentes familiares, no se han investigado previamente los factores de riesgo genéticos de la enfermedad sinusal pilonidal.OBJETIVO:Identificar factores genéticos de riesgo para la enfermedad del seno pilonidal.DISEÑO:Estudio de asociación de genoma completo.CONJUNTOS:Biobanco del Reino Unido, Biobanco FinnGen y Biobanco PennMedicine.PACIENTES:772.072 participantes.MEDIDA DE RESULTADO PRINCIPAL:Las variantes significativas en todo el genoma (p < 5x10-8) se asignaron a genes utilizando la distancia física y la expresión génica en la piel. La correlación genética entre la enfermedad del seno pilonidal y los fenotipos morfométricos, androgénicos y de cabello se estimó con regresión de puntuación LD. Por último, se realizó una aproximación genómica a variantes deletéreas raras predichas en los genes del tallo piloso TCHH, PADI3 y TGM3 para su asociación con la enfermedad del seno pilonidal a través del Biobanco PennMedicine.RESULTADOS:El estudio de asociación de todo el genoma, que incluyó a 2.835 individuos con enfermedad del seno pilonidal, identificó 5 loci significativos en todo el genoma, dando prioridad a HDAC9, TBX15, WARS2, RP11-293M10.1, PRKAR1B, TWIST1, GPATCH2L, NEK9 y EIF2B2, como genes causales putativos; varios de estos genes tienen funciones conocidas en la calvicie y el patrón del cabello. Se observó una correlación significativa entre los antecedentes genéticos de la enfermedad del seno pilonidal y los de los rasgos calvicie de patrón masculino y edad temprana del primer vello facial impulsados por andrógenos. En un análisis de genes candidatos asociados a trastornos capilares sindrómicos, las variantes raras de codificación en TCHH, una causa monogénica del síndrome capilar incombustible, se asociaron a una mayor prevalencia de la enfermedad del seno pilonidal (OR 4,81 [IC del 5%, 2,06-11,2]).LIMITACIONES:Este estudio se limita a la ascendencia europea. Sin embargo, debido a que hay una mayor incidencia de la enfermedad sinusal pilonidal en los hombres de ascendencia europea, este análisis se centra en la población de riesgo.CONCLUSIÓN:El análisis genético de la enfermedad del seno pilonidal identificó una arquitectura genética compartida con la biología del cabello y los rasgos impulsados por andrógenos. Siendo el primer estudio que investiga las bases genéticas de la enfermedad del seno pilonidal, esto proporciona una visión biológica de la conexión, apreciada desde hace tiempo, entre el estado de la enfermedad, el sexo masculino y el cabello. (Traducción-Dr. Aurian Garcia Gonzalez ).

A constrained maximum likelihood approach to developing well-calibrated models for predicting binary outcomes

The added value of candidate predictors for risk modeling is routinely evaluated by comparing the performance of models with or without including candidate predictors. Such comparison is most meaningful when the estimated risk by the two models are both unbiased in the target population. Very often data for candidate predictors are sourced from nonrepresentative convenience samples. Updating the base model using the study data without acknowledging the discrepancy between the underlying distribution of the study data and that in the target population can lead to biased risk estimates and therefore an unfair evaluation of candidate predictors. To address this issue assuming access to a well-calibrated base model, we propose a semiparametric method for model fitting that enforces good calibration. The central idea is to calibrate the fitted model against the base model by enforcing suitable constraints in maximizing the likelihood function. This approach enables unbiased assessment of model improvement offered by candidate predictors without requiring a representative sample from the target population, thus overcoming a significant practical challenge. We study theoretical properties for model parameter estimates, and demonstrate improvement in model calibration via extensive simulation studies. Finally, we apply the proposed method to data extracted from Penn Medicine Biobank to inform the added value of breast density for breast cancer risk assessment in the Caucasian woman population.

Abstract 1105: Genome-first Approach To Rare And Common Variant Risk Of Thoracic Aortic Aneurysm And Dissection

Background: Thoracic aortic aneurysm and dissection (TAAD) can have catastrophic health consequences. Eleven genes have strong or definitive evidence for causing hereditary TAAD (HTAAD). However, patients are seldom tested for rare pathogenic (P) or likely pathogenic (LP) variants in these HTAAD genes, and little is known about their prevalence in the general population. The degree to which common genetic variation associated with TAAD modifies rare variant pathogenicity is unknown. Methods: Penn Medicine Biobank (PMBB) participants volunteered to have electronic health records linked to biospecimen data including DNA that has undergone genome-wide genotyping and whole exome sequencing. P/LP HTAAD gene variants were curated according to American College of Medical Genetics and Genomics standards and analyzed to determine the associated risk of TAAD. A TAAD polygenic risk score (PRS) was derived from a multi-trait genome-wide association study (GWAS) of TAAD and aortic diameter and analyzed to determine the modifying effect this PRS had on rare variant penetrance. Results: Of the 43,731 participants in the analytic cohort, 309 individuals carried a P/LP HTAAD gene variant, 79 (26%) of whom had a diagnosis of TAAD. Among non-carriers, 2,106 (4.9%) had a diagnosis of TAAD. Compared to individuals without a P/LP variant, those with a P/LP HTAAD variant had a 5.4-fold increased risk of a TAAD diagnosis (95% confidence interval [CI] 1.8 to 16.8, P =0.003). Similar results were seen among carriers stratified by individual HTAAD gene. Using a multi-trait GWAS to isolate the diameter-independent common genetic changes linked to TAAD, we constructed a PRS that strongly associated with TAAD in the PMBB (OR 1.70 per 1 s.d. increase in PRS, 95% CI 1.62 to 1.78, P &lt;0.001). Finally, TAAD prevalence was increased among individuals carrying a P/LP HTAAD gene variant in the highest PRS quintile (38.2%, 95% CI 25.4% to 52.3%) compared to carriers in the lowest PRS quintile (8.9%, 95% CI 3.0% to 19.6%) suggesting that common variant risk modifies rare variant TAAD risk. Conclusions: Our results indicate that P/LP HTAAD gene variants confer a 5.4-fold increased risk of TAAD in the population at-large, and that common variant risk may be an important modifier of rare variant TAAD risk.

The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD

The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain. Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort. ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant. Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development.

A genome-first approach to variants in MLXIPL and their association with hepatic steatosis and plasma lipids.

Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear. We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank. Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol. Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.

Polygenic risk score-based phenome-wide association for glaucoma and its impact on disease susceptibility in two large biobanks

BackgroundGlaucoma is a leading cause of worldwide irreversible blindness. Considerable uncertainty remains regarding the association between a variety of phenotypes and the genetic risk of glaucoma, as well as the impact they exert on the glaucoma development.MethodsWe investigated the associations of genetic liability for primary open angle glaucoma (POAG) with a wide range of potential risk factors and to assess its impact on the risk of incident glaucoma. The phenome-wide association study (PheWAS) approach was applied to determine the association of POAG polygenic risk score (PRS) with a wide range of phenotypes in 377, 852 participants from the UK Biobank study and 43,623 participants from the Penn Medicine Biobank study, all of European ancestry. Participants were stratified into four risk tiers: low, intermediate, high, and very high-risk. Cox proportional hazard models assessed the relationship of POAG PRS and ocular factors with new glaucoma events.ResultsIn both discovery and replication set in the PheWAS, a higher genetic predisposition to POAG was specifically correlated with ocular disease phenotypes. The POAG PRS exhibited correlations with low corneal hysteresis, refractive error, and ocular hypertension, demonstrating a strong association with the onset of glaucoma. Individuals carrying a high genetic burden exhibited a 9.20-fold, 11.88-fold, and 28.85-fold increase in glaucoma incidence when associated with low corneal hysteresis, high myopia, and elevated intraocular pressure, respectively.ConclusionGenetic susceptibility to POAG primarily influences ocular conditions, with limited systemic associations. Notably, the baseline polygenic risk for POAG robustly associates with new glaucoma events, revealing a large combined effect of genetic and ocular risk factors on glaucoma incidents.

Association between genetic risk and adherence to healthy lifestyle for developing age-related hearing loss

BackgroundPrevious studies have shown that lifestyle/environmental factors could accelerate the development of age-related hearing loss (ARHL). However, there has not yet been a study investigating the joint association among genetics, lifestyle/environmental factors, and adherence to healthy lifestyle for risk of ARHL. We aimed to assess the association between ARHL genetic variants, lifestyle/environmental factors, and adherence to healthy lifestyle as pertains to risk of ARHL.MethodsThis case–control study included 376,464 European individuals aged 40 to 69 years, enrolled between 2006 and 2010 in the UK Biobank (UKBB). As a replication set, we also included a total of 26,523 individuals considered of European ancestry and 9834 individuals considered of African-American ancestry through the Penn Medicine Biobank (PMBB). The polygenic risk score (PRS) for ARHL was derived from a sensorineural hearing loss genome-wide association study from the FinnGen Consortium and categorized as low, intermediate, high, and very high. We selected lifestyle/environmental factors that have been previously studied in association with hearing loss. A composite healthy lifestyle score was determined using seven selected lifestyle behaviors and one environmental factor.ResultsOf the 376,464 participants, 87,066 (23.1%) cases belonged to the ARHL group, and 289,398 (76.9%) individuals comprised the control group in the UKBB. A very high PRS for ARHL had a 49% higher risk of ARHL than those with low PRS (adjusted OR, 1.49; 95% CI, 1.36–1.62; P < .001), which was replicated in the PMBB cohort. A very poor lifestyle was also associated with risk of ARHL (adjusted OR, 3.03; 95% CI, 2.75–3.35; P < .001). These risk factors showed joint effects with the risk of ARHL. Conversely, adherence to healthy lifestyle in relation to hearing mostly attenuated the risk of ARHL even in individuals with very high PRS (adjusted OR, 0.21; 95% CI, 0.09–0.52; P < .001).ConclusionsOur findings of this study demonstrated a significant joint association between genetic and lifestyle factors regarding ARHL. In addition, our analysis suggested that lifestyle adherence in individuals with high genetic risk could reduce the risk of ARHL.