Genome-wide association studies have been successful mapping loci for individual phenotypes, but ... more Genome-wide association studies have been successful mapping loci for individual phenotypes, but few studies have comprehensively interrogated evidence of shared genetic effects across multiple phenotypes simultaneously. Statistical methods have been proposed for analyzing multiple phenotypes using summary statistics, which enables studies of shared genetic effects while avoiding challenges associated with individual-level data sharing. Adaptive tests have been developed to maintain power against multiple alternative hypotheses because the most powerful single-alternative test depends on the underlying structure of the associations between the multiple phenotypes and a single nucleotide polymorphism (SNP). Here we compare the performance of six such adaptive tests: two adaptive sum of powered scores (aSPU) tests, the unified score association test (metaUSAT), the adaptive test in a mixed-models framework (mixAda) and two principal-component-based adaptive tests (PCAQ and PCO). Our s...
Introduction: Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index common... more Introduction: Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index commonly used in clinical workup of anemia. Macrocytosis, or high MCV, is associated with cardiovascular events in chronic kidney disease patients and all-cause mortality. Genome-wide association studies (GWAS) of MCV have been conducted primarily in European and Asian populations; few have included populations of African or American ancestry. The Multiethnic Genotyping Array (MEGA) was designed to improve variant discovery and fine-mapping in US minorities by better capturing population-specific genetic variation. To identify novel MCV loci and examine evidence of generalization of previously reported MCV loci to populations with African and Amerindian genetic admixture, we conducted a GWAS of African American and Hispanic/Latino Population Architecture using Genomics and Epidemiology (PAGE II) participants on the MEGA array. Methods: We employed Illumina MEGA genotype data to evaluate the as...
Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. Howev... more Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved sub-phenotyping. We hypothesized that unbiased clustering of plaques based on gene expression results in an alternative categorization of late-stage atherosclerotic lesions. We analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These novel plaque phenotypes associated with clinical presentation (p<0.001) and showed differences in cellular compositions. Validation in coronary segments showed that the molecular signature of these plaques was linked to coronary ischemia. One of the plaque types with most severe clinical symptoms pointed to both inflammatory and fibrotic cell lineages. This highlighted plaque phenotype showed high expression of genes involved in active inflammatory processes, neutr...
Red blood cells are the most numerous cell in the body, and clinical measures used to describe th... more Red blood cells are the most numerous cell in the body, and clinical measures used to describe them (RBC traits) are highly polygenic. Hundreds of loci have been identified using traditional genome-wide association study methods. However, the majority of association studies have been performed in European- or East Asian-ancestry populations, and heritability estimates suggest that additional associations remain to be identified. Rare variants, which GWAS are typically underpowered to detect, have been considered as potential contributors to this missing heritability. Of note, European-ancestry populations have both the lowest genetic diversity and the fewest rare variants compared to other ancestry groups. Both the identification of previously unreported loci and the characterization of known loci for complex quantitative traits benefit from inclusive study populations and recently developed association study methods. The objective of this study was to evaluate genetic associations ...
Background: The World Health Organization (WHO) criteria for sudden unexpected death (SUD) descri... more Background: The World Health Organization (WHO) criteria for sudden unexpected death (SUD) describes either witnessed death or unwitnessed death occurring no more than 24 hours after the subject wa...
Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences acro... more Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across several cell types. Genome-wide association studies (GWAS) have identified over 170 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements (CREs). Here, we applied single-cell ATAC-seq to profile 28,316 cells across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants via quantitative trait locus and sequence-based predictive modeling. We identified a number of candidate mechanisms for smooth muscle cell transition states and identified putative binding sites for risk variants. We further employed CRE to gene linkage to nominate disease-associated key driver transcription factors such as PR...
Introduction: Variability within the normal population range of hematocrit is associated with str... more Introduction: Variability within the normal population range of hematocrit is associated with stroke and myocardial infarction. Published GWAS of hematocrit have identified multiple loci, yet few studies have included populations of Hispanic or African descent, thereby limiting opportunities to identify population-specific variants or narrow associated regions for functional analysis. We present a fine-mapping analysis of six previously identified hematocrit loci in African American and Hispanic/Latino participants of the PAGE study. Methods: Approximately 200,000 genotyped or imputed Metabochip variants were examined for association with hematocrit (proportion of whole blood comprising red blood cells) in 19,822 Hispanic/Latino and 19,973 African American participants. SNPs were excluded on a population-specific basis if effective heterozygosity was < 30. Primary and conditional analyses were performed in Plink, ProbABEL, or SuGen; fixed-effects meta-analyses were performed in M...
Background: The biology of platelets_anuclear megakaryocyte fragments required for clotting_is we... more Background: The biology of platelets_anuclear megakaryocyte fragments required for clotting_is well defined, with abnormalities resulting in clotting disorders ranging from asymptomatic to severe. Although platelet count (PLT) is highly heritable (h 2 =0.57 in NHANES), genetic regulation of this trait remains incompletely characterized. In particular, Hispanic Latinos are a diverse population in which the genetic variability of PLT has not been analyzed. We aimed to 1) identify novel loci associated with PLT in participants of HCHS/SoL; and 2) determine if previously identified PLT loci generalize to the Hispanic Latino population. Methods: We performed a genome-wide association study of PLT in 12,491 participants of HCHS/SoL, which includes individuals with Dominican, Puerto Rican, Mexican, Cuban, South American, and Central American ancestral origins residing in the United States. Participants were genotyped on the Illumina SoL Omni2.5M array and imputed to the 1000 Genomes Phase ...
Background: Thousands of genetic variants have been associated with hematological traits, though ... more Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1 × 10−4) that were conditionally distinct from ...
Background Circulating white blood cell and platelet traits are clinically linked to various dise... more Background Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. Results We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple prev...
Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant trai... more Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic popul...
Proceedings of the National Academy of Sciences, 2020
De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in the... more De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significan...
Most genome-wide association and fine-mapping studies to date have been conducted in individuals ... more Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are still limited. In addition to the limited inclusion of these populations in genetic studies, these populations have more complex linkage disequilibrium structure that may reduce the number of variants associated with a phenotype. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with commercial genome-wide genotyping array data. We demonstrate that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhances gene-mapping pow...
Annual Review of Genomics and Human Genetics, 2016
The past decade has seen a technological revolution in human genetics that has empowered populati... more The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinica...
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large mult... more To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10−5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10−9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One...
Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit... more Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was perfor...
Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, baso... more Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, basophils) differ by ethnicity. The genetic factors underlying basal WBC traits in Hispanics/Latinos are unknown. We performed a genome-wide association study of total WBC and differential counts in a large, ethnically diverse US population sample of Hispanics/Latinos ascertained by the Hispanic Community Health Study and Study of Latinos (HCHS/SOL). We demonstrate that several previously known WBC-associated genetic loci (e.g. the African Duffy antigen receptor for chemokines null variant for neutrophil count) are generalizable to WBC traits in Hispanics/Latinos. We identified and replicated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) associated with monocyte count. The common FLT3 variant rs76428106 has a large allele frequency differential between African and non-African populations. We also identified several novel genetic loci involving or r...
The incidence of out-of-hospital sudden unexpected death (OHSUD) in a racially and socioeconomica... more The incidence of out-of-hospital sudden unexpected death (OHSUD) in a racially and socioeconomically diverse population has been inadequately studied. We collated all OHSUDs over a 24-month period among 18- to 64-year olds in Wake County, North Carolina, to investigate geographic and socioeconomic disparity in incidence of OHSUD. An electronic query of Wake County Emergency Medical Services (EMS) identified all EMS attended out-of-hospital deaths. After excluding trauma, expected deaths, and deaths occurring in non-free-living subjects, medical records and medical examiner's reports were reviewed by a committee of cardiologists to make the determination of OHSUD. Victims were geocoded to census tracts, and demographic and socioeconomic data were obtained from the 2014 American Community Survey and 2010 US Census. Incidence was examined by sociodemographic group with univariate analysis and multivariable regression. There were 397 OHSUDs, and 53% of census tracts had >1 event....
Genome-wide association studies have been successful mapping loci for individual phenotypes, but ... more Genome-wide association studies have been successful mapping loci for individual phenotypes, but few studies have comprehensively interrogated evidence of shared genetic effects across multiple phenotypes simultaneously. Statistical methods have been proposed for analyzing multiple phenotypes using summary statistics, which enables studies of shared genetic effects while avoiding challenges associated with individual-level data sharing. Adaptive tests have been developed to maintain power against multiple alternative hypotheses because the most powerful single-alternative test depends on the underlying structure of the associations between the multiple phenotypes and a single nucleotide polymorphism (SNP). Here we compare the performance of six such adaptive tests: two adaptive sum of powered scores (aSPU) tests, the unified score association test (metaUSAT), the adaptive test in a mixed-models framework (mixAda) and two principal-component-based adaptive tests (PCAQ and PCO). Our s...
Introduction: Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index common... more Introduction: Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index commonly used in clinical workup of anemia. Macrocytosis, or high MCV, is associated with cardiovascular events in chronic kidney disease patients and all-cause mortality. Genome-wide association studies (GWAS) of MCV have been conducted primarily in European and Asian populations; few have included populations of African or American ancestry. The Multiethnic Genotyping Array (MEGA) was designed to improve variant discovery and fine-mapping in US minorities by better capturing population-specific genetic variation. To identify novel MCV loci and examine evidence of generalization of previously reported MCV loci to populations with African and Amerindian genetic admixture, we conducted a GWAS of African American and Hispanic/Latino Population Architecture using Genomics and Epidemiology (PAGE II) participants on the MEGA array. Methods: We employed Illumina MEGA genotype data to evaluate the as...
Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. Howev... more Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved sub-phenotyping. We hypothesized that unbiased clustering of plaques based on gene expression results in an alternative categorization of late-stage atherosclerotic lesions. We analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These novel plaque phenotypes associated with clinical presentation (p<0.001) and showed differences in cellular compositions. Validation in coronary segments showed that the molecular signature of these plaques was linked to coronary ischemia. One of the plaque types with most severe clinical symptoms pointed to both inflammatory and fibrotic cell lineages. This highlighted plaque phenotype showed high expression of genes involved in active inflammatory processes, neutr...
Red blood cells are the most numerous cell in the body, and clinical measures used to describe th... more Red blood cells are the most numerous cell in the body, and clinical measures used to describe them (RBC traits) are highly polygenic. Hundreds of loci have been identified using traditional genome-wide association study methods. However, the majority of association studies have been performed in European- or East Asian-ancestry populations, and heritability estimates suggest that additional associations remain to be identified. Rare variants, which GWAS are typically underpowered to detect, have been considered as potential contributors to this missing heritability. Of note, European-ancestry populations have both the lowest genetic diversity and the fewest rare variants compared to other ancestry groups. Both the identification of previously unreported loci and the characterization of known loci for complex quantitative traits benefit from inclusive study populations and recently developed association study methods. The objective of this study was to evaluate genetic associations ...
Background: The World Health Organization (WHO) criteria for sudden unexpected death (SUD) descri... more Background: The World Health Organization (WHO) criteria for sudden unexpected death (SUD) describes either witnessed death or unwitnessed death occurring no more than 24 hours after the subject wa...
Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences acro... more Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across several cell types. Genome-wide association studies (GWAS) have identified over 170 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements (CREs). Here, we applied single-cell ATAC-seq to profile 28,316 cells across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants via quantitative trait locus and sequence-based predictive modeling. We identified a number of candidate mechanisms for smooth muscle cell transition states and identified putative binding sites for risk variants. We further employed CRE to gene linkage to nominate disease-associated key driver transcription factors such as PR...
Introduction: Variability within the normal population range of hematocrit is associated with str... more Introduction: Variability within the normal population range of hematocrit is associated with stroke and myocardial infarction. Published GWAS of hematocrit have identified multiple loci, yet few studies have included populations of Hispanic or African descent, thereby limiting opportunities to identify population-specific variants or narrow associated regions for functional analysis. We present a fine-mapping analysis of six previously identified hematocrit loci in African American and Hispanic/Latino participants of the PAGE study. Methods: Approximately 200,000 genotyped or imputed Metabochip variants were examined for association with hematocrit (proportion of whole blood comprising red blood cells) in 19,822 Hispanic/Latino and 19,973 African American participants. SNPs were excluded on a population-specific basis if effective heterozygosity was < 30. Primary and conditional analyses were performed in Plink, ProbABEL, or SuGen; fixed-effects meta-analyses were performed in M...
Background: The biology of platelets_anuclear megakaryocyte fragments required for clotting_is we... more Background: The biology of platelets_anuclear megakaryocyte fragments required for clotting_is well defined, with abnormalities resulting in clotting disorders ranging from asymptomatic to severe. Although platelet count (PLT) is highly heritable (h 2 =0.57 in NHANES), genetic regulation of this trait remains incompletely characterized. In particular, Hispanic Latinos are a diverse population in which the genetic variability of PLT has not been analyzed. We aimed to 1) identify novel loci associated with PLT in participants of HCHS/SoL; and 2) determine if previously identified PLT loci generalize to the Hispanic Latino population. Methods: We performed a genome-wide association study of PLT in 12,491 participants of HCHS/SoL, which includes individuals with Dominican, Puerto Rican, Mexican, Cuban, South American, and Central American ancestral origins residing in the United States. Participants were genotyped on the Illumina SoL Omni2.5M array and imputed to the 1000 Genomes Phase ...
Background: Thousands of genetic variants have been associated with hematological traits, though ... more Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1 × 10−4) that were conditionally distinct from ...
Background Circulating white blood cell and platelet traits are clinically linked to various dise... more Background Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. Results We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple prev...
Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant trai... more Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic popul...
Proceedings of the National Academy of Sciences, 2020
De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in the... more De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significan...
Most genome-wide association and fine-mapping studies to date have been conducted in individuals ... more Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are still limited. In addition to the limited inclusion of these populations in genetic studies, these populations have more complex linkage disequilibrium structure that may reduce the number of variants associated with a phenotype. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with commercial genome-wide genotyping array data. We demonstrate that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhances gene-mapping pow...
Annual Review of Genomics and Human Genetics, 2016
The past decade has seen a technological revolution in human genetics that has empowered populati... more The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinica...
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large mult... more To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10−5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10−9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One...
Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit... more Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was perfor...
Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, baso... more Circulating white blood cell (WBC) counts (neutrophils, monocytes, lymphocytes, eosinophils, basophils) differ by ethnicity. The genetic factors underlying basal WBC traits in Hispanics/Latinos are unknown. We performed a genome-wide association study of total WBC and differential counts in a large, ethnically diverse US population sample of Hispanics/Latinos ascertained by the Hispanic Community Health Study and Study of Latinos (HCHS/SOL). We demonstrate that several previously known WBC-associated genetic loci (e.g. the African Duffy antigen receptor for chemokines null variant for neutrophil count) are generalizable to WBC traits in Hispanics/Latinos. We identified and replicated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) associated with monocyte count. The common FLT3 variant rs76428106 has a large allele frequency differential between African and non-African populations. We also identified several novel genetic loci involving or r...
The incidence of out-of-hospital sudden unexpected death (OHSUD) in a racially and socioeconomica... more The incidence of out-of-hospital sudden unexpected death (OHSUD) in a racially and socioeconomically diverse population has been inadequately studied. We collated all OHSUDs over a 24-month period among 18- to 64-year olds in Wake County, North Carolina, to investigate geographic and socioeconomic disparity in incidence of OHSUD. An electronic query of Wake County Emergency Medical Services (EMS) identified all EMS attended out-of-hospital deaths. After excluding trauma, expected deaths, and deaths occurring in non-free-living subjects, medical records and medical examiner's reports were reviewed by a committee of cardiologists to make the determination of OHSUD. Victims were geocoded to census tracts, and demographic and socioeconomic data were obtained from the 2014 American Community Survey and 2010 US Census. Incidence was examined by sociodemographic group with univariate analysis and multivariable regression. There were 397 OHSUDs, and 53% of census tracts had >1 event....
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Papers by Chani Hodonsky