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PubMed2026

Prevalence and Clinical Impact of Pathogenic Variants in Cardiomyopathy Genes Among Individuals with Cardiac Conduction Disorders.

IMPORTANCE: Cardiac conduction disorders have traditionally been regarded as a secondary manifestation of underlying structural heart diseases. However, isolated conduction disorders may precede the onset of heart failure (HF) suggesting shared mechanisms. OBJECTIVE: To evaluate the prevalence and clinical significance of pathogenic/likely pathogenic (P/LP) rare variants in cardiomyopathy genes among individuals with conduction disorders. DESIGN SETTING AND PARTICIPANTS: Biobank analysis of 192,834 participants with whole genome sequence data from Vanderbilt's BioVU and 353,092 participants from the All of Us Research Program (AoU). Participants with primary conduction disorder (left bundle branch block [LBBB], right bundle branch block [RBBB], high-grade atrioventricular block [AVB]) were identified after excluding secondary causes. EXPOSURES: P/LP variants in cardiomyopathy genes. MAIN OUTCOMES AND MEASURES: Primary outcome was P/LP carrier status by age and HF status. Secondary outcomes included incident HF and composite ventricular arrhythmias/sudden cardiac death/mortality (VA/SCD/mortality). RESULTS: Among 16,959 participants with conduction disorders in BioVU and 13,442 in AoU, 432 (2.6%) and 206 (1.5%) were P/LP carriers, respectively. Conduction disorder was independently associated with carrier status (BioVU p<0.001; AoU p=0.005). Carrier probability varied by age at conduction disorder onset and HF status. Among participants with HF at age 30 years, predicted carrier probability for LBBB was 7.5% in BioVU and 20.2% in AoU; for high-grade AVB, 7.7% and 8.5%, respectively, compared with 3.7% and 2.9% among those with HF without conduction disorder. P/LP carrier status among participants with conduction disorders was associated with increased risk of incident HF (BioVU p<0.001; AoU p<0.001) and ventricular arrhythmia/sudden death/mortality (BioVU p<0.001; AoU p<0.001). Carriers also demonstrated increased susceptibility to conduction disorder following HF diagnosis, including more than two-fold higher risk of third-degree AVB (BioVU aOR 2.48, 95% CI 1.85-3.32; AoU aOR 2.26, 95% CI 1.35-3.80). CONCLUSIONS: Adults with primary conduction disorders have an increased prevalence of P/LP variants in cardiomyopathy genes, which is most pronounced with diagnoses at early ages of adulthood. Furthermore, there is evidence of an interaction between P/LP carrier status and conduction disorder to increase HF risk and composite cardiovascular outcomes, underscoring the potential role of genetic evaluation in patients with primary conduction disorders to inform long-term outcomes.

Journal Article↗

PubMed2025

Polygenic Associations between Motor Behaviour, Neuromotor Traits, and Active Music Engagement in Four Cohorts.

Phenotypic investigations have shown that actively engaging with music, i.e., playing a musical instrument or singing may be protective of motor decline in aging. For example, music training associated with enhanced sensorimotor skills accompanied by changes in brain structure and function. Although it is possible that the benefits of active music engagement "transfer" to benefits in the motor domain, it is also possible that the genetic architecture of motor behaviour and the motor system structure may influence active music engagement. This study investigated whether polygenic scores (PGS) for five behavioural motor traits, 12 neuromotor structural brain traits, and seven rates of change in brain structure traits trained from existing discovery genome-wide association studies (GWAS) predict active music engagement outcomes in four independent cohorts of unrelated individuals of European ancestry: the Canadian Longitudinal Study on Aging (CLSA; N=22,198), Wisconsin Longitudinal Study (WLS; N=4,605), Vanderbilt's BioVU Repository (BioVU; N=6,150), and Vanderbilt's Online Musicality study (OM; N=1,559). Results were meta-analyzed for each PGS main effect across outcomes and cohorts, revealing that PGS for a faster walking pace was associated with higher amounts of active music engagement. Within CLSA, a higher PGS for walking pace was associated with greater odds of engaging with music. Findings suggest a shared genetic architecture between motor function and active music engagement. Future intervention-based research should consider the genetic underpinnings of motor behavior when evaluating the effects of music engagement on motor function across the lifespan.

BioVU↗

PubMed2024

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

IMPORTANCE: 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. OBJECTIVE: To interrogate the clinical traits and diseases associated with BAG3 coding variation. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Carrier status for BAG3 coding variants. MAIN OUTCOMES AND MEASURES: Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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.

Humans↗

PubMed2026

Inherited Predisposition to Increased Systemic Inflammation Predicts a Broad Class of Disease Phenotypes.

Chronic, low-grade systemic inflammation is a polygenic trait captured with the INFLA-score, a composite of C-reactive protein, platelet count, leukocyte count, and granulocyte-to-lymphocyte ratio. We derived a polygenic risk score from the INFLA-score (iPRS) in a multi-ancestry population from the UK Biobank (n=421,368), then evaluated and used it in a phenome-wide association study among participants in the All of Us Research Program (AoU). The multi-ancestry iPRS was tested for association with the INFLA-score in AoU (N=4,833 with biomarker data) via linear regression, adjusting for age, sex, and genetically-determined principal components (PCs) and with 2,821 phecodeX-defined phenotypes in AoU (N=265,068) via logistic regression, adjusting for sex, age, EHR length, race, ethnicity and PCs. The iPRS predicted the INFLA-score (R-squared=0.026, beta=0.980, p<2x10-16) and was associated with 47 phenotypes (Bonferroni-corrected p<0.05). The strongest associations were with blood-related phenotypes: elevated white blood cell count (OR=1.19, p=3.85x10-66), thrombocytopenia (OR=0.86, p=5.70x10-44), platelet defects (OR=0.86, p=2.47x10-43), neutropenia (OR= 0.86, p=5.52x10-18), myeloproliferative disorder (OR= 1.2, p=2.77x10-15). Others included celiac disease (OR=0.713, p=2.98x10-46), ankylosing spondylitis (OR=1.4, p=1.33 x 10-17), hypertension (OR=1.04, p=4.56x10-15), rheumatoid arthritis (OR=1.09, p=1.02x10-13), hematuria (OR=1.05, p=1.96x10-10). Removing major-histocompatibility-complex SNPs abolished associations with known autoimmune diseases, while all other associations remained. We replicated 17 (42.5%) of 40 significant phenotypes available in the Vanderbilt University Medical Center's BioVU. Our findings demonstrate that systemic inflammation can be predicted using the iPRS across multiple ancestries, and the iPRS is associated with numerous clinical endpoints. This multi-ancestry iPRS may have future utility in stratifying risk for inflammation-driven conditions across diverse populations.

Journal Article↗

PubMed2019

CYP2D6 genotype and adverse events to risperidone in children and adolescents.

BACKGROUND: There are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children. METHODS: Children ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: For analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03). CONCLUSION: Children with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.

Adolescent↗

PubMed2026

Multi-ancestry genetic architecture of heart failure subtypes.

Heart failure (HF) affects 6.7 million people in the US and includes two major subtypes, HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), with distinct genetic architectures. We meta-analyze genome-wide association studies (GWAS) of 38,781 HFrEF cases, 38,163 HFpEF cases, and 526,135 controls across European, African, Hispanic, and Asian ancestries using the Million Veteran Program and Vanderbilt University DNA Databank (BioVU). We identify 46 genome-wide significant loci for HFrEF (9 novel) and 3 loci for HFpEF (1 novel). Four HFrEF loci are detected in African ancestry participants near CD36, SPI1, TRIM48, and SPNS3, with lead SNPs showing low risk-allele frequencies in European populations. In the all-cause HF meta-analysis (200,070 cases, 2,076,466 controls), we identify 136 loci (12 novel). Gene-based tests, tissue enrichment, transcriptome-wide association, and fine-mapping implicate vascular, metabolic, and TGF-β/Smad signaling pathways and nominate candidate causal genes, clarifying shared and subtype-specific risk across ancestries.

Humans↗

PubMed2025

Genetic relationships between systemic lupus erythematosus and a positive antinuclear antibody test in the absence of autoimmune disease.

OBJECTIVE: We defined the genetic factors associated with a positive ANA test (ANA+) in the absence of autoimmune disease and tested the association with SLE. METHODS: Using a case-control design, we performed a genome-wide association study (GWAS) in individuals of European ancestry without an autoimmune disease who had ANA tested as part of clinical care from DNA biobanks linked to de-identified electronic medical records: BioVU and Electronic Medical Records and Genomics. GWAS results were meta-analysed and single nucleotide polymorphism (SNP) heritability was calculated. A polygenic risk score (PRS) for ANA+ and for SLE was constructed and compared in patients with SLE, ANA+ and ANA negative (ANA-) individuals without autoimmune disease and general controls who never had ANA testing performed. RESULTS: A total of 7287 individuals of European ancestry were included in the meta-analyses (2169 ANA+ and 5118 ANA-); an SNP upstream of the TSBP1 in the HLA locus (rs1967688) was associated with ANA+ (p=4.84×10-8). SNP heritability for ANA+ was low (h2 SNP= 0.04), and the PRS for ANA+ was not significantly different in ANA+ and ANA- individuals. In contrast, the PRS for SLE was significantly higher in SLE compared with ANA+ individuals (p<2.2×10-16) but did not differ among ANA+, ANA- and general control groups (p=0.17). CONCLUSIONS: ANA+ occurring in the absence of autoimmune disease has a genetic association with the HLA region, but overall heritability is low. In addition, few SLE-associated SNPs were associated with ANA+, and the PRS for SLE was not associated with ANA+, indicating limited genetic overlap.

Humans↗

PubMed2025

Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways.

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Journal Article↗