Biology subjects

Munroe, P. B.

Publications and source records attributed to Munroe, P. B..

4 recordsLinked to original sources

bioRxiv2025

An epigenomic investigation of atrial fibrillation in a matched left and right atrial human cohort

As the most prevalent cardiac arrythmia, atrial fibrillation is an important contributor to cardiovascular morbidity and mortality. Human population findings increasingly support its complex genetic architecture, with most genetic association signals for atrial fibrillation found in the non-coding genome. In this study, we integrated genome-wide histone modification, gene expression and DNA methylation levels in a paired left and right atrial cohort comprising permanent atrial fibrillation patients and sinus rhythm controls. First, we first identified epigenomic regions enriched in histone H3 lysine 27 acetylation (H3K27ac) across left and right atria from patients and controls, and associated them with differentially expressed genes to derive a set of dysregulated candidate loci - including NPPB and SCX. Second, by incorporating an independent replication cohort, we were able to validate gene expression and epigenomic differences for a subset of these candidate loci. Third, we profiled base-resolution DNA methylation levels and identified differentially-methylated regions (DMRs) between atrial fibrillation and sinus rhythm samples. Integration of these data with histone modification levels and gene expression allowed us to propose epigenetic mechanisms underlying transcriptomic and epigenomic changes across dysregulated loci, such as disruption of transcription factor binding by DNA methylation at the LRRC4B locus. The data and analyses we report constitute a systematic investigation of gene regulatory alterations across the left and right atria in permanent atrial fibrillation.

genomics↗

bioRxiv2023

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

Genome-wide association studies of blood pressure (BP) have identified >1000 loci but the effector genes and biological pathways at these loci are mostly unknown. Using published meta-analysis summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with [≥]2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, DBH) and previously unreported BP candidate genes (NRIP1, MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs, and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, tissue expression data and literature review, we provide consolidated evidence for 394 BP candidate genes for future functional validation and identifies several new drug targets.

genetics↗

bioRxiv2020

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups using 1 degree of freedom (1df) interaction and 2df joint tests. Primary multi-ancestry analyses in 62,969 individuals in stage 1 identified 3 novel loci that were replicated in an additional 59,296 individuals in stage 2, including rs7955964 (FIGNL2/ANKRD33) showing significant 1df interactions with long sleep duration and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) showing significant 1df interactions with short sleep duration (Pint < 5x10-8). Secondary ancestry-specific two-stage analyses and combined stage 1 and 2 analyses additionally identified 23 novel loci that need external replication, including 3 and 5 loci showing significant 1df interactions with long and short sleep duration, respectively (Pint < 5x10-8). Multiple genes mapped to our 26 novel loci have known functions in sleep-wake regulation, nervous and cardiometabolic systems. We also identified new gene by long sleep interactions near five known BP loci ([≤]1Mb) including NME7, FAM208A, MKLN1, CEP164, and RGL3/ELAVL3 (Pint < 5x10-8). This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

genomics↗

bioRxiv2019

KCND3 is a novel susceptibility locus for early repolarization

The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.\n\nIn this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

genetics↗