Amelia Weber Hall

Broad Institute of MIT and Harvard · Epigenomics Program

Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the de...

BACKGROUND Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular...

Background: Despite the critical role of the cardiovascular system, our understanding of its cellular and transcriptional diversity remains limited. We therefore sought to characterize the cellular composition, phenotypes, molecular pathways, and communication networks between cell types at the tissue and sub-tissue level across the cardiovascular...

To broaden our understanding of bradyarrhythmias and diseases of the cardiac conduction system, we performed cross-sectional multi-ancestry genome-wide association study meta-analyses in up to 1.3 million individuals for sinus node dysfunction (SND), distal conduction disease (DCD), and pacemaker implantation (PM). We evaluated the biological relev...

This protocol describes how to isolate and purify nuclei from solid tissue for use in single-cell library construction methods. The resulting nuclei are suitable for a variety of single-cell assays such as droplet-based methods like 10x Genomics Chromium and hybridization-based methods like SHARE-seq. Through sequencing we have verified that the re...

Background: ZFHX3, a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice....

An updated version of the protocol SHARE-seq, as used by the Epigenomics Platform and Gene Regulation Observatory at the Broad Institute in the service of data production for the IGVF project. Link to the original paper and protocol here: https://www.sciencedirect.com/science/article/pii/S0092867420312538

Left ventricular mass is a risk marker for cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance is the gold-standard for left ventricular mass estimation, but is challenging to obtain at scale. Here, we use deep learning to enable genome-wide association study of cardiac magnetic resonance-derived left ve...

Ischemic cardiomyopathy (ICM) is the leading cause of heart failure worldwide, yet the cellular and molecular signature of this disease is largely unclear. Using single-nucleus RNA sequencing (snRNA-seq) and integrated computational analyses, we profile the transcriptomes of over 99,000 human cardiac nuclei from the non-infarct region of the left v...

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, e...

Background: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequ...

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57...

Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known. Our da...

Increased left ventricular (LV) mass (LVM) and LV hypertrophy (LVH) are risk markers for adverse cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance (CMR) is the gold standard for LVM estimation, but is challenging to obtain at scale, which has limited the power of prior genetic analyses. In the current...

Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals,...

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, e...

Background - Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between ECG intervals and rare genetic variation at a population level are poorly understood. Methods - Using a discovery sample of 29,000...

Background: Rare sequence variation in genes underlying the long QT syndrome (LQTS) and common polygenic variation influence QT interval duration. It is unclear how rare and common variation contribute to QT interval duration in the general population. Objectives: Investigate monogenic and polygenic contributions to QT interval duration and the rol...

Background Many human diseases are known to have a genetic contribution. While genome-wide studies have identified many disease-associated loci, it remains challenging to elucidate causal genes. In contrast, exome sequencing provides an opportunity to identify new disease genes and large-effect variants of clinical relevance. We therefore sought to...

Introduction: Electrocardiogram (ECG) intervals are quantitative and heritable endophenotypes for arrhythmias and sudden cardiac death (SCD). Studying rare sequence variation related to ECG intervals may help identify the genetic underpinnings of cardiac conduction and SCD. Methods: Using a discovery sample of 29,000 individuals with whole-genome s...

Background - Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the non-coding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molec...

Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 indivi...

Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of t...

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have no...

Background: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low input RNA-sequencing have allowed definitions of cellular tra...

The aorta is the largest blood vessel in the body, and enlargement or aneurysm of the aorta can predispose to dissection, an important cause of sudden death. While rare syndromes have been identified that predispose to aortic aneurysm, the common genetic basis for the size of the aorta remains largely unknown. By leveraging a deep learning architec...

Introduction: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low input RNA-sequencing have allowed definitions of cellular t...

Rationale: Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in TTN and early-onset AF. Objective: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population. Metho...

Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2 . Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 with varying conservation in m...

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality 1,2 . We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, disco...

Most disease-associated variants identified by population based genetic studies are non-coding, which compromises finding causative genes and mechanisms. Presumably they interact through looping with nearby genes to modulate transcription. Hi-C provides the most complete and unbiased method for genome-wide identification of potential regulatory int...

Glioblastoma multiforme (GBM) can be clustered by gene expression into four main subtypes associated with prognosis and survival, but enhancers and other gene-regulatory elements have not yet been identified in primary tumors. Here, we profiled six histone modifications and CTCF binding as well as gene expression in primary gliomas and identified c...

Significance Calmodulin is essential for sensing intracellular Ca ²⁺ in eukaryotic cells. Calmodulin modulates hundreds of effectors, and it has a highly conserved protein sequence. Humans have three identical copies, but a change in either the protein sequence or the protein expression level of any one of the three copies can cause life-threatenin...

Purpose Non-pulmonary vein (non-PV) triggers and left atrial (LA) scars perpetuate atrial fibrillation (AF) and limit the success rate of catheter ablation. In order to understand the genetic basis of these risk factors, we examined the association of selected single nucleotide polymorphisms (SNPs) with scar and non-PV triggers. Methods Four hundr...

Background: Prolongation of the PR interval in the electrocardiogram (ECG) is known to be associated with increased risk of atrial fibrillation (AF). We examined the association of selected single nucleotide polymorphisms (SNPs) with PR interval in AF patients. Methods: Four hundred AF patients undergoing catheter ablation were prospectively enroll...

Purpose Non-pulmonary vein (non-PV) triggers and left atrial (LA) scars perpetuate atrial fibrillation (AF) and limit the success rate of catheter ablation. In order to understand the genetic basis of these risk factors, we examined the association of selected single nucleotide polymorphisms (SNPs) with scar and non-PV triggers. Methods Four hundre...

Introduction: Earlier evidences support the origin of ectopic beats from non-pulmonary vein (non-PV) areas that initiate and maintain AF and elimination of these triggers is known to provide better arrhythmia-free survival. Of the different types, non-paroxysmal AF (NPAF) are more prevalently associated with non-PV drivers. Although emerging data o...

Introduction: Earlier studies have demonstrated that some AF patients develop spontaneous atrial scarring that leads to genesis and perpetuation of the arrhythmia. However, it is still unclear why it happens in some and not in others. Therefore, we hypothesized that the atrial scar phenotype is associated with certain specific genetic variants and...

In this paper we use eQTL mapping to identify associations between gene dysregulation and single nucleotide polymorphism (SNP) genotypes in glioblastoma multiforme (GBM). A set of 532,954 SNPs was evaluated as predictors of the expression levels of 22,279 expression probes. We identified SNPs associated with fold change in expression level rather t...

Single nucleotide polymorphisms (SNPs) have been associated with many aspects of human development and disease, and many non-coding SNPs associated with disease risk are presumed to affect gene regulation. We have previously shown that SNPs within transcription factor binding sites can affect transcription factor binding in an allele-specific and h...

CTCF allele-specific binding at Pilot 2 SNPs. SNPs with an FDR corrected bias P value of less than 0.05 are included. Each tab contains information for one individual.

Figure S1. Diagram of SNP discovery pipeline. Figure S2. Numbers of Pilot 2 SNPs rediscovered correlate with ChIP-seq coverage. For each trio cell line, the percentage of Pilot 2 SNPs rediscovered with ChIP-seq data is plotted together with percent of the genome with at least 5X coverage from ChIP-seq. Figure S3. Validation of de novo discovered SN...

CTCF allele-specific binding at SNPs discovered de novo from CTCF ChIP-seq. SNPs with an FDR corrected bias P value of less than 0.05 are included. Each tab contains information for one individual.

Bacteria use a signaling and regulatory system called "quorum sensing" to alter their gene expressions in response to the concentration of neighboring bacteria and to environmental conditions that make collective activity favorable for bacteria. P. aeruginosa is an opportunistic human pathogen that uses quorum sensing to govern processes such as vi...

Small conductance calcium-activated potassium (SK) channels respond to intracellular Ca(2+) via constitutively associated calmodulin (CaM). Previous studies have proposed a modular design for the interaction between CaM and SK channels. The C-lobe and the linker of CaM are thought to regulate the constitutive binding, whereas the N-lobe binds Ca(2+...

Large, long-lived species experience more lifetime cell divisions and hence a greater risk of spontaneous tumor formation than smaller, short-lived species. Large, long-lived species are thus expected to evolve more elaborate tumor suppressor systems. In previous work, we showed that telomerase activity coevolves with body mass, but not lifespan, i...