Eric R Gamazon

• PhD
• Associate Professor with tenure, VUMC; Life Member, Clare Hall, Cambridge at Vanderbilt University Med Ctr; Clare Hall, University of Cambridge

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease pheno...

Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body m...

Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression...

Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation m...

We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying po...

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel s...

The biological functions of extragenic enhancer RNAs and their impact on disease risk remain relatively underexplored. In this work, we develop in silico models of genetically regulated expression of enhancer RNAs across 49 cell and tissue types, characterizing their degree of genetic control. Leveraging the estimated genetically regulated expressi...

INTRODUCTION Gliomas are the most common primary malignant brain tumor in adults. Genome-wide association studies (GWAS) have identified 25 loci associated with glioma risk. Using transcriptome-wide association study (TWAS) methodology with joint-tissue imputation, our group investigated 3 genetic repositories to identify genes predictive of the gl...

Introduction: The prevalence of hepatic steatosis—a central and early phenotype in multi-system metabolic dysfunction—is increasing in parallel with the obesity pandemic, calling for novel approaches for prevention and treatment. Hypothesis: We hypothesized that the circulating proteome may reflect cell specific mechanisms of hepatic steatosis. Met...

Current genetic discovery methods are largely restricted to profiling circulating molecules or genetic architecture, limited in use of tissue-based molecular genetics to identify pathogenic and therapeutic targets. Here, we leverage a multi-level genetic discovery platform integrating population-level proteomics with functional genomic analyses bas...

Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cel...

Root causal gene expression levels – or root causal genes for short – correspond to the initial changes to gene expression that generate patient symptoms as a downstream effect. Identifying root causal genes is critical towards developing treatments that modify disease near its onset, but no existing algorithms attempt to identify root causal genes...

Polygenic severe obesity (body mass index [BMI] ≥40 kg/m²) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA...

G6PC3 deficiency is a monogenic immunometabolic disorder that causes severe congenital neutropenia type 4. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican descent. Based on the...

Single-cell transcriptome data can provide insights into how genetic variation influences biological processes involved in human physiology and disease. However, the identification of gene-level associations in distinct cell types faces several challenges, including the limited reference resources from population-scale studies, data sparsity in sin...

Aims/hypothesis Microvascular dysfunction contributes to insulin resistance. CD36, a fatty acid transporter and modulator of insulin signalling, is abundant in microvascular endothelial cells. Humans carrying the minor allele (G) of CD36 coding variant rs3211938 have 50% reduced CD36 expression and show endothelial dysfunction. We aimed to determin...

Background We present the NeuroimaGene resource as an R package designed to assist researchers in identifying genes and neurologic features relevant to psychiatric and neurological health. While recent studies have identified hundreds of genes as potential components of pathophysiology in neurologic and psychiatric disease, interpreting the physiol...

Research on brain expression quantitative trait loci (eQTLs) has illuminated the genetic underpinnings of schizophrenia (SCZ). Yet most of these studies have been centered on European populations, leading to a constrained understanding of population diversities and disease risks. To address this gap, we examined genotype and RNA-seq data from Afric...

An understanding of human brain individuality requires the integration of data on brain organization across people and brain regions, molecular and systems scales, as well as healthy and clinical states. Here, we help advance this understanding by leveraging methods from computational genomics to integrate large-scale genomic, transcriptomic, neuro...

Background Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC). Methods Multi-modal regulatory elements in periph...

Root causal genes correspond to the first gene expression levels perturbed during pathogenesis by genetic or non-genetic factors. Targeting root causal genes has the potential to alleviate disease entirely by eliminating pathology near its onset. No existing algorithm discovers root causal genes from observational data alone. We therefore propose t...

Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies...

Cell death mediated by genetically defined signaling pathways influences the health and dynamics of all tissues, however the tissue specificity of cell death pathways and the relationships between these pathways and human disease are not well understood. We analyzed the expression profiles of an array of 44 cell death genes involved in apoptosis, n...

Dysfunction of endothelial insulin delivery to muscle associates with insulin resistance. CD36, a fatty acid transporter and modulator of insulin signaling is abundant in endothelial cells, especially in capillaries. Humans with inherited 50% reduction in CD36 expression have endothelial dysfunction but whether it is associated with insulin resista...

Research on brain expression quantitative trait loci (eQTLs) has illuminated the genetic underpinnings of schizophrenia (SCZ). Yet, the majority of these studies have been centered on European populations, leading to a constrained understanding of population diversities and disease risks. To address this gap, we examined genotype and RNA-seq data f...

Transcriptome‐wide association study (TWAS) methodologies aim to identify genetic effects on phenotypes through the mediation of gene transcription. In TWAS, in silico models of gene expression are trained as functions of genetic variants and then applied to genome‐wide association study (GWAS) data. This post‐GWAS analysis identifies gene‐trait as...

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dat...

The root causes of disease correspond to the initial perturbations to a biological system that generate patient symptoms as a downstream effect. Identifying root causal genes is critical towards developing treatments that modify disease at its onset. However, RNA-sequencing (RNA-seq) data introduces a host of challenges such as measurement error, h...

Background Dysregulation of white matter tracts (WMTs) in the brain is a common feature of Alzheimer’s Disease (AD) and is associated with declining cognitive function. Two neuroimaging measures, Fractional Anisotropy (FA) and isometric volume fraction (ISOVF) represent WM integrity through quantifying organization of axon bundles and changes in ex...

Background Genetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regi...

Background Alzheimer’s Disease (AD) is a heritable, neurodegenerative disease. Most AD cases can be categorized as Late Onset Alzheimer’s Disease (LOAD) cases, which are polygenic. Genome Wide Association Studies (GWAS) of LOAD have identified several associated single nucleotide polymorphisms (SNPs). These variants are in 75 genetic loci, and have...

Background Dysregulation of white matter tracts (WMTs) in the brain is a common feature of Alzheimer’s Disease (AD) and is associated with declining cognitive function. Two neuroimaging measures, Fractional Anisotropy (FA) and isometric volume fraction (ISOVF) represent WM integrity through quantifying organization of axon bundles and changes in ex...

Organisms maintain metabolic homeostasis through the combined functions of small molecule transporters and enzymes. While many of the metabolic components have been well-established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association s...

Background Common and rare variants contribute to the etiology of complex traits. However, the extent to which the phenotypic effects of common and rare variants involve shared molecular mediators remains poorly understood. The question is essential to the basic and translational goals of the science of genomics, with critical basic-science, method...

Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Drugs with human genetic evidence are more likely to advance successfully through clinical trials towards FDA approval. Single gene-based drug repositioning methods have been implemented, but approaches leveraging a broad spectrum of m...

Single-cell transcriptome data can provide insights into how genetic variation influences biological processes involved in human biology and disease. However, the identification of gene-level associations in distinct cell types faces several challenges, including the limited reference resource from population scale studies, data sparsity in single-...

Raynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three...

Treatments ideally mitigate pathogenesis, or the detrimental effects of the root causes of disease. However, existing definitions of treatment effect fail to account for pathogenic mechanism. We therefore introduce the Treated Root causal Effects (TRE) metric which measures the ability of a treatment to modify root causal effects. We leverage TREs...

Integrating gene expression across tissues and cell types is crucial for understanding the coordinated biological mechanisms that drive disease and characterize homoeostasis. However, traditional multi-tissue integration methods either cannot handle uncollected tissues or rely on genotype information, which is often unavailable and subject to priva...

Anxiety disorders are a group of prevalent and heritable neuropsychiatric diseases. We previously conducted a genome-wide association study (GWAS) which identified genomic loci associated with anxiety; however, the biological consequences underlying the genetic associations are largely unknown. Integrating GWAS and functional genomic data may impro...

We introduce CoRE-BED, a framework trained using 19 epigenomic features encompassing 33 major cell and tissue types to predict cell-type-specific regulatory function. CoRE-BED's interpretability facilitates causal inference and functional prioritization. CoRE-BED identifies nine functional classes de-novo, capturing both known and completely new re...

Apoptotic, necroptotic, and pyroptotic cell death pathways are attractive and druggable targets for many human diseases, however the tissue specificity of these pathways and the relationship between these pathways and human disease is poorly characterized. Understanding the impact of modulating cell death gene expression on the human phenome could...

Salt-sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen presenting cells (APCs), resulting...

Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus...

Imaging features associated with neuropsychiatric traits can provide valuable insights into underlying pathophysiology. Using data from the UK biobank, we perform tissue-specific TWAS on over 3,500 neuroimaging phenotypes to generate a publicly accessible resource detailing the neurophysiologic consequences of gene expression. As a comprehensive ca...

Deep Mutational Scanning (DMS) has enabled multiplexed measurement of mutational effects on protein properties, including kinematics and self-organization, with unprecedented resolution. However, potential bottlenecks of DMS characterization include experimental design, data quality, and depth of mutational coverage. Here, we apply deep learning to...

Background Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. The largest global meta-analysis of XF...

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different bi...

Genomic data is often processed in batches and analyzed together to save time. However, it is challenging to combine multiple large VCFs and properly handle imputation quality and missing variants due to limitations of available tools. To address these concerns, we developed IMMerge, a Python-based tool that takes advantage of multiprocessing to re...

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individual...

Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary s...

Genome-wide association studies (GWAS) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis associating serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subg...

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents represent...

The Global Biobank Meta-analysis Initiative (GBMI), through its diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ancestry study populations across biobanks, GBMI presents unique challenges in implementing statistical genetics met...

Germline genetic variations can alter cellular differentiation, potentially impacting the response of immune cells to inflammatory challenges. Current variant- and gene-based methods in mouse and human models have established associations with disease phenotypes; however, the underlying mechanisms at the cellular level are less well-understood. Imm...

A bstract Integrating gene expression across scales and tissues is crucial for understanding the biological mechanisms that drive disease and characterise homeostasis. However, traditional multi-tissue integration methods cannot handle uncollected tissues or rely on genotype information, which is subject to privacy concerns and often unavailable. T...

Deep Mutational Scanning (DMS) experiments have been performed on SARS-CoV-2’s spike receptor binding domain and human ACE2 zinc-binding peptidase domain – both central players in viral infection and evolution and antibody evasion - quantifying how mutations impact biochemical phenotypes. We modeled biochemical phenotypes from massively parallel as...

Objective: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. Methods: Ninety-eight patients with hemodynamically defined PAH...

INTRODUCTION Trigeminal neuralgia (TN) is a debilitating neuropathic pain disease. While many clinical risk factors have been associated with TN, the genetic basis is largely unknown and no genome-wide association studies (GWAS) have been performed. Here we perform the first GWAS for TN and conduct a fixed-effect meta-analysis including 1,188 TN ca...

We develop a symbolic regression framework for extracting the governing mathematical expressions from observed data. The evolutionary approach, faiGP, is designed to leverage the properties of a function algebra that have been encoded into a grammar, providing a theoretical guarantee of universal approximation and a way to minimize bloat. In this f...

Background Global genetic correlation analysis has provided valuable insight into the shared genetic basis between psychiatric and substance use disorders. However, little is known about which regions disproportionately contribute to the global correlation. Methods We used Local Analysis of [co]Variant Annotation to calculate bivariate local genet...

We developed an integrative transcriptomic, evolutionary, and causal inference framework for a deep region-level analysis, which integrates several published approaches and a new summary-statistics-based methodology. To illustrate the framework, we applied it to understanding the host genetics of COVID-19 severity. We identified putative causal gen...

Type 2 diabetes is a complex, systemic disease affected by both genetic and environmental factors. Previous research has identified genetic variants associated with type 2 diabetes risk, however gene regulatory changes underlying progression to metabolic dysfunction are still largely unknown. We investigated RNA expression changes that occur during...

Genome-wide association studies (GWASs) have identified thousands of risk loci for psychiatric and substance use phenotypes, however the biological consequences of these loci remain largely unknown. We performed a transcriptome-wide association study of 10 psychiatric disorders and 6 substance use phenotypes (GWAS sample size range, N = 9725–807,55...

Alzheimer's Disease (AD) is a debilitating form of dementia with a high prevalence in the global population and a large burden on the community and health care systems. AD's complex pathobiology consists of extracellular β-amyloid deposition and intracellular hyperphosphorylated tau. Comprehensive mutational analyses can generate a wealth of knowle...

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally. There is disparity in POAG prevalence and manifestations across ancestries. We identify novel and unique genetics that underlie POAG risk in different ancestries by performing meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) wi...

Late-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic m...

With the increasing availability of biobank-scale datasets that incorporate both genomic data and electronic health records, many associations between genetic variants and phenotypes of interest have been discovered. Polygenic risk scores (PRS), which are being widely explored in precision medicine, use the results of association studies to predict...

Here, we performed a comprehensive intra-tissue and inter-tissue multilayer network analysis of the human transcriptome. We generated an atlas of communities in gene co-expression networks in 49 tissues (GTEx v8), evaluated their tissue specificity, and investigated their methodological implications. UMAP embeddings of gene expression from the comm...

The Global Biobank Meta-analysis Initiative (GBMI), through its genetic and demographic diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ethnic study populations across biobanks, the GBMI provides a distinct set of challenges in...

Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism1. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions2. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involv...

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36 −/− ), with Cd36 deletion in parie...

Detangling gene-disease connections Many diseases are at least partially due to genetic causes that are not always understood or targetable with specific treatments. To provide insight into the biology of various human diseases as well as potential leads for therapeutic development, Pietzner et al . undertook detailed, genome-wide proteogenomic map...

Background and Objectives To integrate genome-wide association study data with tissue-specific gene expression information to identify coexpression networks, biological pathways, and drug repositioning candidates for Alzheimer disease. Methods We integrated genome-wide association summary statistics for Alzheimer disease with tissue-specific gene...

A large proportion of heritability for prostate cancer risk remains unknown. Transcriptome‐wide association study combined with validation comparing overall levels will help to identify candidate genes potentially playing a role in prostate cancer development. Using data from the Genotype‐Tissue Expression Project, we built genetic models to predic...

Glutathione (GSH) is a small molecule thiol abundantly present in all eukaryotes with key roles in oxidative metabolism. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions. GSH is exclusively synthesized in the cytosol, yet the molecular machinery involved...

Background Genome-wide association studies (GWAS) have identified over 56 susceptibility loci associated with Alzheimer’s disease (AD), but the genes responsible for these associations remain largely unknown. Methods We performed a large transcriptome-wide association study (TWAS) leveraging modified UTMOST (Unified Test for MOlecular SignaTures)...

Alzheimer’s disease (ad) adversely affects the health, quality of life and independence of patients. There is a critical need to identify novel blood gene biomarkers for ad risk assessment. We performed a transcriptome-wide association study to identify biomarker candidates for ad risk. We leveraged two sets of gene expression prediction models of...

Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization too...

Detection of molecular quantitative trait loci (QTL) facilitates mechanistic insights into disease-associated genetic variants. A new study describes BaseQTL, which exploits allele-specific expression to map molecular QTL from sequencing reads even without paired genotype data.

We conducted PrediXcan analysis of hydrocephalus risk in ten neurological tissues and whole blood. Decreased expression of MAEL in the brain was significantly associated (Bonferroni-adjusted p < 0.05) with hydrocephalus. PrediXcan analysis of brain imaging and genomics data in the independent UK Biobank (N = 8,428) revealed that MAEL expression in...

A question of fundamental biological significance is to what extent the expression of a subset of genes can be used to recover the full transcriptome, with important implications for biological discovery and clinical application. To address this challenge, we propose two novel deep learning methods, PMI and GAIN-GTEx, for gene expression imputation...

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v...

Motivation Genome-wide association studies have successfully identified multiple independent genetic loci that harbour variants associated with human traits and diseases, but the exact causal genes are largely unknown. Common genetic risk variants are enriched in non-protein-coding regions of the genome and often affect gene expression (expression...

Background: While many clinical risk factors of trigeminal neuralgia (TN) have been identified, the genetic basis of TN is largely unknown. Here, we perform the first genome-wide association study (GWAS) for TN using three independent DNA biobanks: BioVU, the UK Biobank, and Finngen. Objective: To elucidate the genetic basis of TN. Methods: Using G...