Tanika N Kelly

• Tulane University

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropi...

Background: Many present analyses of Hispanic/Latino populations in epidemiologic research aggregate all members of this ethnic group, despite immense diversity in genetic backgrounds, environment, and culture between and across Hispanic/Latino background groups. Using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we examined the...

BACKGROUND Coronary artery calcium (CAC) is heterogeneous in older age and is incompletely explained by traditional atherosclerotic cardiovascular disease risk factors. The extremes of subclinical atherosclerosis burden are strongly associated with either a low or high 10-year risk of incident atherosclerotic cardiovascular disease, respectively. H...

Introduction We investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications. Methods We conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 7,913) using linear regression and...

BACKGROUND Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking.METHODS Using liquid chromatography-mass spectrometry (LC-MS), we repeatedly measured 1,...

Exposure to toxic metals impacts obesity and type 2 diabetes (T2DM) risk. Yet, the underlying mechanisms remain largely unknown. Gut microbiota has been strongly associated with progression of cardiometabolic risk. To determine whether high metal exposures and gut dysbiosis interact to promote metabolic dysregulation and cardiometabolic risk, we as...

Background Cardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have chronic kidney disease (CKD). We sought to develop a proteomics-based risk score for card...

Rationale & Objective In the general population, neighborhood socioeconomic status (SES) has been found to be associated with cardiovascular risk, but this relationship has not been well studied among patients with chronic kidney disease (CKD). This study seeked to evaluate the association between neighborhood SES and cardiovascular outcomes in a C...

INTRODUCTION Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown. METHODS We conducted time‐to‐event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency...

BACKGROUND The blood pressure (BP) etiologic study is complex due to multifactorial influences, including genetic, environmental, lifestyle, and their intricate interplays. We used a metabolomics approach to capture internal pathways and external exposures and to study BP regulation mechanisms after well-controlled dietary interventions. METHODS I...

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other t...

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model,...

Although epigenetic age acceleration (EAA) might serve as a molecular signature of childhood cardiovascular disease (CVD) risk factors and further promote midlife subclinical CVD, few studies have comprehensively examined these life course associations. This study sought to test whether childhood CVD risk factors predict EAA in adulthood and whethe...

Introduction: The US Environment Protection Agency has proposed National Primary Drinking Water Regulation for six per- and polyfluoroalkyl substances including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). The health effects of the two chemicals need to be thoroughly evaluated. In addition, few studies have investigated inter...

Introduction: Patients with chronic kidney disease (CKD) are at substantially increased risk of dementia. Clonal hematopoiesis of indeterminate potential (CHIP), caused by clonal expansion of blood cells with somatic mutations in certain driver genes, is an established risk factor for cardiovascular diseases, including cerebral vascular disease. In...

Background: Metabolomics may identify novel biomarkers for predicting, detecting, and managing diabetes. We evaluated the association of novel metabolites with diabetes, prediabetes, and continuous glycemic outcomes (fasting plasma glucose (FPG); hemoglobin A1c (HbA1c)) using data from the Bogalusa Heart Study (BHS) and Atherosclerosis Risk in Comm...

Introduction: Hypertension (HTN) is a leading cause of cardiovascular disease and premature death. A few circulating metabolites have been associated with blood pressure or HTN; however, findings from multi-ethnic populations are limited. Methods: Discovery analysis included eight population-based cohorts from the Trans-Omics for Precision Medicine...

Introduction: Inosine, a naturally occurring purine nucleotide, has been used as a dietary supplement to enhance overall health. An emerging study in a rat model has indicated that inosine holds promise as a potential treatment for atherosclerosis by reducing cholesterol-driven inflammation and improving vascular function, providing a foundational...

Introduction: While the emergence of amyloid-clearing treatments for Alzheimer’s disease is promising, the identification of additional therapeutic options for Alzheimer’s disease and related dementia syndromes (AD/ADRD) remains urgent. Plasma proteins represent a class of actionable drug targets AD/ADRD treatment. Yet, the role of the blood proteo...

Introduction: Cardiovascular disease (CVD) remains the leading cause of mortality in the US, highlighting the need for novel approaches to its prediction, prevention, and management. Epigenetic age acceleration (EAA), or increased DNA methylation-based age relative to chronological age, is a promising biomarker of disease risk. While previous studi...

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure tra...

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model,...

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome seq...

Background Genomic study of cognition decline while considering baseline cognition and lifestyle behaviors is scarce. We aimed to evaluate the impact of a polygenic score for general cognition on cognition decline rate, while considering baseline cognition and lifestyle behaviors, among the general population and people with diabetes, a patient gro...

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropi...

Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increa...

Scope: This study aims to discover metabolites of dietary carbohydrate, soy and milk protein supplements and evaluate their roles in blood pressure (BP) regulation in the protein and blood pressure (ProBP), a cross-over trial. Methods and results: Plasma metabolites are profiled at pre-trial baseline and after 8 weeks of supplementation with car...

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine...

Background: Dairy consumption is related to chronic disease risk, yet the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake. Objectives: We aimed to identify associations between dietary intake of dairy (total dairy, low-fat dairy, an...

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage...

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality globally. Although CVD events do not typically manifest until older adulthood, CVD develops gradually across the life-course, beginning with the elevation of risk factors observed as early as childhood or adolescence and the emergence of subclinical disease that can occur in...

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare “clumping-and-thresholding” (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, includin...

Background: Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney func...

Introduction: Mechanisms for metabolically healthy obesity (MHO) are not well studied. Methods: We performed cross-sectional analyses among 1,261 participants of the Bogalusa Heart Study 2013-2016 survey. A total of 887 known serum metabolites were profiled using an untargeted approach. Participants who met all the following five criteria were cons...

Background: Despite known associations of epigenetic age acceleration (EAA), or increased DNA methylation (DNAm)-based age relative to chronological age, with Alzheimer’s disease, few studies have investigated the relation of EAA with midlife cognitive function. We examined cross-sectional associations of EAA with cognition among the 1,252 middle-a...

Introduction: Current guidelines recommend ≥2 servings of fish/week for the prevention of atherosclerotic cardiovascular disease (ASCVD). However, a recent large meta-analysis suggested that the benefit may exist only for persons with a prior ASCVD event. Whether coronary artery calcium (CAC) can help to identify individuals who are likely to benef...

Introduction: Uncontrolled high dose aspirin use impairs kidney function. Short-term low dose aspirin treatment has also been associated with kidney function in older patients. We aimed to evaluate the association of regular aspirin use with kidney function in middle-aged adults and to identify factors modifying the association. Methods: We perform...

Introduction: There is a lack of objective biomarkers of dietary intake. Untargeted studies can unbiasedly identify dairy biomarkers and inform the creation of robust dietary assessment tools that integrate questionnaire and biospecimen data. Methods: Dairy products from interviewer-administered questionnaires were categorized as either low-fat or...

Background: The incidence of chronic kidney disease (CKD) is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. Methods: We conducted a genome-wide association study among 1,738 CKD patients, mainly from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kid...

Background: We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD). Methods: Plasma samples were selected from 2 sources: (a) 24 participants from the Chronic Renal Insufficiency Cohor...

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-an...

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries⁵. Here we leveraged global genetic...

Chronic kidney disease (CKD) was responsible for 1.2 million deaths globally in 2016. Despite the large and growing burden of CKD, treatment options are limited and generally only preserve kidney function. Characterizing molecular precursors to incident and progressive CKD could point to critically needed prevention and treatment strategies. Clonal...

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing...

Introduction: In the Protein and Blood Pressure (ProBP) trial, milk and soy protein supplements reduced blood pressure (BP) compared to carbohydrate intervention. We investigated the underlying mechanisms influencing the effects. Methods: Serum metabolites were profiled at pre-trial baseline and after supplementation with carbohydrate, soy protein,...

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance....

Background: The epithelial Na+ channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in SCNN1A, SCNN1B, and SCNN1G, genes encoding the α, β, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and SCNN1D, which e...

Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large‐scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previ...

Genetic information may help to identify individuals at increased risk for hypertension in early life, prior to the manifestation of elevated blood pressure (BP) values. We examined 369 Black and 832 White Bogalusa Heart Study (BHS) participants recruited in childhood and followed for approximately 37 years. The multi-ancestry genome-wide polygenic...

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic i...

Background and objectives Mitochondrial DNA copy number is a biomarker of mitochondrial function, which has been hypothesized to contribute to pathogenesis of CKD through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. The prospective association of mitochondrial DNA copy number with CKD progression has not been previo...

Background: Genetic information may help to identify individuals in childhood who are at increased risk for cardiometabolic disease. Methods: We included 1201 BHS (Bogalusa Heart Study) participants (832 White participants and 369 Black participants) who were followed up to 42.3 years, starting at a mean age of 9.8 years. A validated genome-wide...

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision...

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS i...

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predispose...

Background and Aims Identify novel metabolite associations with blood pressure (BP) salt-sensitivity and hypertension. Methods and Results The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Replication study includes 698 Chinese participants who underwent a 3-day baseline examination followed by a 7-day low-sodium feeding and 7-day hig...

Objective: The authors hypothesize that an untargeted metabolomics study will identify novel mechanisms underlying smoking-associated weight loss. Methods: This study performed cross-sectional analyses among 1,252 participants in the Bogalusa Heart Study and assessed 1,202 plasma metabolites for mediation effects on smoking-BMI associations. Sig...

Introduction: 2-aminoadipic acid (2-AAA) secreted during adipogenesis is a novel marker for diabetes. Hypothesis: 2-AAA mediates the associations between body mass index (BMI) and metabolic measures, and the effect of 2-AAA can be modified by environmental factors. Methods: We performed cross-sectional analyses among all 1,252 participants in the B...

Background: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive classes to achieve blood pressure (BP) control. The estimated prevalence of aTRH from population-based studies is ~12-15% among adults with hypertension (HTN). Individuals with aTRH have an increased risk for cardiovascular even...

African Americans (AAs) experience a high burden of hypertension but have been underrepresented in genetic studies of blood pressure. We performed common and rare variant genome-wide association studies (GWAS) of systolic (SBP) and diastolic (DBP) blood pressure, pulse pressure and hypertension in 95,457 AAs from the Million Veteran Program and Con...

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate ana...

We aimed to evaluate associations of baseline telomere length with overall and annual change in estimated glomerular filtration rate (eGFR) and trajectory of kidney function during an 8-year follow-up. A total of 3,964 participants of the Health and Retirement Study (HRS) were included. We identified three trajectory groups of kidney function: cons...

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,...

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is a biomarker of mitochondrial function that has been associated with chronic kidney disease (CKD) and all-cause mortality in several community-based studies. However, there has been little research on mtDNA-CN and progression of CKD. Hypothesis: We hypothesized that higher mtDNA-CN will be as...

Background and objectives Moderate coffee consumption has been associated with lower risk of CKD; however, the exact biologic mechanisms underlying this association are unknown. Metabolomic profiling may identify metabolic pathways that explain the association between coffee and CKD. The goal of this study was to identify serum metabolites associat...

Background and Purpose Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Prec...

Deceleration in the decline of cardiovascular disease mortality has been observed recently in the US. We aimed to examine the recent secular trends of cardiovascular health metrics in the US general population. A total of 32,832 adults aged ≥20 years from the National Health and Nutrition Examination Surveys 2007 to 2018 were included in this analy...

Background: We used summary statistics from previously-published GWAS of systolic and diastolic BP and of hypertension to construct Polygenic Risk Scores (PRS) to predict hypertension across diverse populations. Methods: We used 10,314 participants of diverse ancestry from BioMe to train trait-specific PRS. We implemented a novel approach to select...

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and inte...

Objective A significant proportion of persons with metabolic syndrome (MetS), prediabetes, or type 2 diabetes (T2D) do not develop atherosclerotic cardiovascular disease (ASCVD). We sought to determine whether discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-C may help to explain heterogeneity in ASCVD risk among persons with me...

Background In individuals with chronic kidney disease (CKD), healthy dietary patterns are inversely associated with CKD progression. Metabolomics, an approach that measures many small molecules in biofluids, can identify biomarkers of healthy dietary patterns. Objectives We aimed to identify known metabolites associated with greater adherence to 4...

Background Early identification of healthy arterial aging versus premature atherosclerosis is important for optimal atherosclerotic cardiovascular disease risk stratification and prevention. We sought to identify predictors for the long‐term absence of carotid plaque among young adults. Methods and Results We included 508 participants from the Bog...

Introduction: In individuals with chronic kidney disease (CKD), healthy dietary patterns are inversely associated with CKD progression. Metabolomics, an approach which measures many small molecules in biofluids, can identify biomarkers of healthy dietary patterns and elucidate metabolic pathways underlying diet-disease associations. Hypothesis: We...

Introduction: Many studies identified that smokers had lower body mass index (BMI) than non-smokers, but the underlying mechanisms are not well understood. Hypothesis: An untargeted metabolomics study will identify novel mechanisms underlying smoking associated weight loss. Methods: We performed cross-sectional analyses among all 248 current smoker...

Introduction: A significant proportion of persons with metabolic syndrome, prediabetes, or type 2 diabetes do not develop atherosclerotic cardiovascular disease (ASCVD). Discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-cholesterol (LDL-C) may help to explain underlying heterogeneity in ASCVD risk among these individuals. Hypothe...

Introduction: Most genetic variants for chronic kidney disease (CKD) have been identified in non-coding regions, with functional roles that are difficult to interpret. Hypothesis: A whole exome sequencing study focusing on coding variants will reveal novel mechanisms of kidney function and CKD. Methods: We performed whole exome sequencing analyses...

Introduction: Early differentiation of healthy arterial aging versus premature atherosclerosis is important for optimal atherosclerotic cardiovascular disease (ASCVD) risk stratification and prevention. We sought to identify predictors for the long-term absence of carotid plaque in young adults. Hypothesis: Calcium and phosphate are found in excess...

More than half of US adults have hypertension by 40 years of age and a subsequent increase in atherosclerotic cardiovascular disease risk. Dietary sodium and potassium are intricately linked to the pathophysiology of hypertension. However, blood pressure responses to dietary sodium and potassium, phenomena known as salt and potassium sensitivity of...

Cross-sectional studies have reported that high sodium sensitivity is more common among individuals with hypertension. Experimental studies have also reported various animal models with sodium-resistant hypertension. It is unknown, however, whether sodium sensitivity and resistance precede the development of hypertension. We conducted a feeding stu...

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonizati...

Background In the general population, genetic risk for high BP has been associated with cardiovascular disease, but not kidney function or incident CKD. These relationships have not been studied longitudinally in participants with CKD. We examined whether BP genetic risk predicts cardiovascular disease and kidney disease progression in patients wit...

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03280-1.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated eve...

Background and aims A large proportion of statin eligible candidates have a baseline absence of coronary artery calcium (CAC) and low 10-year atherosclerotic cardiovascular disease (ASCVD) risk. We sought to determine the proportion of statin eligible individuals who had long-term healthy arterial aging (persistent CAC=0) and their examined 15-year...