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1.
Nature ; 590(7845): 290-299, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33568819

RESUMEN

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.


Asunto(s)
Variación Genética/genética , Genoma Humano/genética , Genómica , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisión , Citocromo P-450 CYP2D6/genética , Haplotipos/genética , Heterocigoto , Humanos , Mutación INDEL , Mutación con Pérdida de Función , Mutagénesis , Fenotipo , Polimorfismo de Nucleótido Simple , Densidad de Población , Medicina de Precisión/normas , Control de Calidad , Tamaño de la Muestra , Estados Unidos , Secuenciación Completa del Genoma/normas
2.
Stroke ; 53(3): 875-885, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34727735

RESUMEN

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 Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1. CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.


Asunto(s)
Sitios Genéticos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Medicina de Precisión , Grupos Raciales/genética , Accidente Cerebrovascular/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Secuenciación Completa del Genoma
3.
Am J Epidemiol ; 190(10): 1977-1992, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33861317

RESUMEN

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical 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 harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.


Asunto(s)
Estudios de Asociación Genética/métodos , Fenómica/métodos , Medicina de Precisión/métodos , Agregación de Datos , Humanos , Difusión de la Información , National Heart, Lung, and Blood Institute (U.S.) , Fenotipo , Evaluación de Programas y Proyectos de Salud , Estados Unidos
4.
Ann Neurol ; 81(3): 383-394, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27997041

RESUMEN

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales/genética , Cromosomas Humanos Par 16/genética , Estudio de Asociación del Genoma Completo , Accidente Cerebrovascular/genética , Dedos de Zinc/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Sitios Genéticos , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Accidente Vascular Cerebral Lacunar/genética
5.
N Engl J Med ; 368(6): 503-12, 2013 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-23388002

RESUMEN

BACKGROUND: Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS: We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS: One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).


Asunto(s)
Estenosis de la Válvula Aórtica/genética , Válvula Aórtica/patología , Calcinosis/genética , Enfermedades de las Válvulas Cardíacas/genética , Lipoproteína(a)/genética , Polimorfismo de Nucleótido Simple , Anciano , Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/etnología , Femenino , Estudio de Asociación del Genoma Completo , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/etnología , Humanos , Modelos Lineales , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/patología , Tomografía Computarizada por Rayos X
6.
PLoS Genet ; 8(4): e1002640, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22511882

RESUMEN

Using ~60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By projection of principal components (PCs) of ancestry to samples from the HapMap phase III and the Human Genome Diversity Panel (HGDP), we show the first two PCs quantify the Caucasian, African, and Native American origins, while the third and fourth PCs bring out an axis that aligns with known South-to-North geographic location of HGDP Native American samples and further separates MESA Mexican versus Central/South American samples along the same axis. Using k-means clustering computed from the first four PCs, we define four subgroups of the MESA Hispanic cohort that show close agreement with self-identification, labeling the clusters as primarily Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. To demonstrate our recommendations for genetic analysis in the MESA Hispanic cohort, we present pooled and stratified association analysis of triglycerides for selected SNPs in the LPL and TRIB1 gene regions, previously reported in GWAS of triglycerides in Caucasians but as yet unconfirmed in Hispanic populations. We report statistically significant evidence for genetic association in both genes, and we further demonstrate the importance of considering population substructure and genetic heterogeneity in genetic association studies performed in the United States Hispanic population.


Asunto(s)
Aterosclerosis , Estudios de Asociación Genética , Hispánicos o Latinos/genética , Polimorfismo de Nucleótido Simple/genética , Triglicéridos , Aterosclerosis/epidemiología , Aterosclerosis/genética , Población Negra/genética , Análisis por Conglomerados , Proyecto Mapa de Haplotipos , Humanos , Indígenas Norteamericanos/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Lipoproteína Lipasa/genética , Grupos de Población/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Triglicéridos/sangre , Triglicéridos/genética , Estados Unidos , Población Blanca/genética
7.
JAMA ; 312(17): 1764-71, 2014 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-25344734

RESUMEN

IMPORTANCE: Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE: To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS: Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461). MAIN OUTCOMES AND MEASURES: Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS: The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02). CONCLUSIONS AND RELEVANCE: Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.


Asunto(s)
Estenosis de la Válvula Aórtica/genética , Calcio/análisis , LDL-Colesterol/sangre , LDL-Colesterol/genética , Predisposición Genética a la Enfermedad , Cardiopatías Congénitas/genética , Enfermedades de las Válvulas Cardíacas/genética , Polimorfismo de Nucleótido Simple , Anciano , Válvula Aórtica/química , Estenosis de la Válvula Aórtica/epidemiología , Aterosclerosis/epidemiología , Aterosclerosis/genética , Enfermedad de la Válvula Aórtica Bicúspide , Causalidad , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Cardiopatías Congénitas/epidemiología , Enfermedades de las Válvulas Cardíacas/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estados Unidos/epidemiología
8.
BMC Med Genet ; 14: 75, 2013 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-23870195

RESUMEN

BACKGROUND: Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. METHODS: We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. RESULTS: Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. CONCLUSIONS: While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.


Asunto(s)
Aterosclerosis/genética , Negro o Afroamericano/genética , Enfermedad de la Arteria Coronaria/genética , Calcificación Vascular/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Proteínas de Microfilamentos/genética , Polimorfismo de Nucleótido Simple
9.
Cell Genom ; 3(8): 100359, 2023 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-37601969

RESUMEN

Multi-omics datasets are becoming more common, necessitating better integration methods to realize their revolutionary potential. Here, we introduce multi-set correlation and factor analysis (MCFA), an unsupervised integration method tailored to the unique challenges of high-dimensional genomics data that enables fast inference of shared and private factors. We used MCFA to integrate methylation markers, protein expression, RNA expression, and metabolite levels in 614 diverse samples from the Trans-Omics for Precision Medicine/Multi-Ethnic Study of Atherosclerosis multi-omics pilot. Samples cluster strongly by ancestry in the shared space, even in the absence of genetic information, while private spaces frequently capture dataset-specific technical variation. Finally, we integrated genetic data by conducting a genome-wide association study (GWAS) of our inferred factors, observing that several factors are enriched for GWAS hits and trans-expression quantitative trait loci. Two of these factors appear to be related to metabolic disease. Our study provides a foundation and framework for further integrative analysis of ever larger multi-modal genomic datasets.

10.
Nat Genet ; 55(10): 1651-1664, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37770635

RESUMEN

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.


Asunto(s)
Aterosclerosis , Enfermedad de la Arteria Coronaria , Humanos , Aterosclerosis/genética , Población Negra/genética , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Pueblo Europeo/genética
11.
Hum Genet ; 131(2): 275-87, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21805149

RESUMEN

Cohort studies typically sample unrelated individuals from a population, although family members of index cases may also be recruited to investigate shared familial risk factors. Recruitment of family members may be incomplete or ancillary to the main cohort, resulting in a mixed sample of independent family units, including unrelated singletons and multiplex families. Multiple methods are available to perform genome-wide association (GWA) analysis of binary or continuous traits in families, but it is unclear whether methods known to perform well on ascertained pedigrees, sibships, or trios are appropriate in analysis of a mixed unrelated cohort and family sample. We present simulation studies based on Multi-Ethnic Study of Atherosclerosis (MESA) pedigree structures to compare the performance of several popular methods of GWA analysis for both quantitative and dichotomous traits in cohort studies. We evaluate approaches suitable for analysis of families, and combined the best performing methods with population-based samples either by meta-analysis, or by pooled analysis of family- and population-based samples (mega-analysis), comparing type 1 error and power. We further assess practical considerations, such as availability of software and ability to incorporate covariates in statistical modeling, and demonstrate our recommended approaches through quantitative and binary trait analysis of HDL cholesterol (HDL-C) in 2,553 MESA family- and population-based African-American samples. Our results suggest linear modeling approaches that accommodate family-induced phenotypic correlation (e.g., variance-component model for quantitative traits or generalized estimating equations for dichotomous traits) perform best in the context of combined family- and population-based cohort GWAS.


Asunto(s)
Estudios de Cohortes , Familia , Estudio de Asociación del Genoma Completo/métodos , Grupos de Población , Humanos , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
12.
Cell Genom ; 2(8)2022 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-36119389

RESUMEN

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting. While informed by our experiences as researchers affiliated with the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, these recommendations are applicable to basic and translational genomic research in diverse populations with genome-wide data. Moving forward, considerable collaborative effort will be required to ensure that race, ethnicity, and ancestry are described and used appropriately to generate scientific knowledge that yields broad and equitable benefit.

13.
Sci Adv ; 8(14): eabl6579, 2022 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-35385311

RESUMEN

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, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

14.
Nat Genet ; 51(11): 1580-1587, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31659325

RESUMEN

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.


Asunto(s)
Aterosclerosis/patología , Predisposición Genética a la Enfermedad , Histona Desacetilasas/metabolismo , Histona Desacetilasas/fisiología , Contracción Muscular , Músculo Liso Vascular/patología , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología , Calcificación Vascular/patología , Anciano , Animales , Aorta/metabolismo , Aorta/patología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Estudios de Cohortes , Femenino , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Estudio de Asociación del Genoma Completo , Histona Desacetilasas/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Músculo Liso Vascular/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple , Proteínas Represoras/genética , Calcificación Vascular/genética , Calcificación Vascular/metabolismo
15.
Sci Rep ; 7(1): 10348, 2017 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-28871152

RESUMEN

Hypertension prevalence varies between ethnic groups, possibly due to differences in genetic, environmental, and cultural determinants. Hispanic/Latino Americans are a diverse and understudied population. We performed a genome-wide association study (GWAS) of blood pressure (BP) traits in 12,278 participants from the Hispanics Community Health Study/Study of Latinos (HCHS/SOL). In the discovery phase we identified eight previously unreported BP loci. In the replication stage, we tested these loci in the 1982 Pelotas Birth Cohort Study of admixed Southern Brazilians, the COGENT-BP study of African descent, women of European descent from the Women Health Initiative (WHI), and a sample of European descent from the UK Biobank. No loci met the Bonferroni-adjusted level of statistical significance (0.0024). Two loci had marginal evidence of replication: rs78701042 (NGF) with diastolic BP (P = 0.008 in the 1982 Pelotas Birth Cohort Study), and rs7315692 (SLC5A8) with systolic BP (P = 0.007 in European ancestry replication). We investigated whether previously reported loci associated with BP in studies of European, African, and Asian ancestry generalize to Hispanics/Latinos. Overall, 26% of the known associations in studies of individuals of European and Chinese ancestries generalized, while only a single association previously discovered in a people of African descent generalized.


Asunto(s)
Presión Sanguínea/genética , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Carácter Cuantitativo Heredable , Adulto , Anciano , Alelos , Mapeo Cromosómico , Femenino , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Vigilancia en Salud Pública , Reproducibilidad de los Resultados , Estados Unidos/epidemiología , Estados Unidos/etnología
16.
J Am Coll Cardiol ; 69(24): 2941-2948, 2017 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-28619195

RESUMEN

BACKGROUND: Mitral annular calcium (MAC), commonly identified by cardiac imaging, is associated with cardiovascular events and predisposes to the development of clinically important mitral valve regurgitation and mitral valve stenosis. However, its biological determinants remain largely unknown. OBJECTIVES: The authors sought to evaluate whether a genetic predisposition to elevations in plasma lipids is associated with the presence of MAC. METHODS: The authors used 3 separate Mendelian randomization techniques to evaluate the associations of lipid genetic risk scores (GRS) with MAC in 3 large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE-RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The authors provided cross-ethnicity replication in the MESA Hispanic-American participants. RESULTS: MAC was present in 1,149 participants (20.4%). In pooled analyses across all 3 cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit: 1.73; 95% confidence interval [CI]: 1.24 to 2.41; p = 0.0013). Neither low- nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross-ethnicity analyses among the MESA Hispanic-Americans cohort (OR per triglyceride GRS unit: 2.04; 95% CI: 1.03 to 4.03; p = 0.04). In joint meta-analysis across all included cohorts, the triglyceride GRS was associated with MAC (OR per triglyceride GRS unit: 1.79; 95% CI: 1.32 to 2.41; p = 0.0001). The results were robust to several sensitivity analyses that limit both known and unknown forms of genetic pleiotropy. CONCLUSIONS: Genetic predisposition to elevated triglyceride levels was associated with the presence of MAC, a risk factor for clinically significant mitral valve disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant mitral valve disease requires further study.


Asunto(s)
Calcinosis/genética , Predisposición Genética a la Enfermedad , Insuficiencia de la Válvula Mitral/genética , Válvula Mitral/diagnóstico por imagen , Polimorfismo Genético , Triglicéridos/genética , Anciano , Calcinosis/diagnóstico , Calcinosis/metabolismo , Femenino , Estudios de Seguimiento , Variación Genética , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Insuficiencia de la Válvula Mitral/diagnóstico , Insuficiencia de la Válvula Mitral/metabolismo , Estudios Prospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos X , Triglicéridos/sangre
17.
Arthritis Rheumatol ; 69(6): 1294-1305, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28076899

RESUMEN

OBJECTIVE: The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. METHODS: We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. RESULTS: We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10-42 , P = 3 × 10-14 , and P = 9 × 10-10 , respectively), and several novel suggestive regions (those with 2 or more associations at P < 1 × 10-5 ). Two regions have been previously implicated in autoimmune disease: KLRG1 (P = 6 × 10-7 [Asian cluster]) and SH2D2A (P = 2 × 10-6 [all participants]). We observed striking differences between the associations in Europeans and Asians, with high heterogeneity especially in the MHC; representative single-nucleotide polymorphisms from established and suggestive regions had highly significant differences in the allele frequencies in the study populations. We showed that SSA/SSB autoantibody production and the labial salivary gland focus score criteria were associated with the first worldwide principal component, indicative of higher non-European ancestry (P = 4 × 10-15 and P = 4 × 10-5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. CONCLUSION: Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes.


Asunto(s)
Pueblo Asiatico/genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Síndrome de Sjögren/genética , Población Blanca/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Autoanticuerpos/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Factores Reguladores del Interferón/genética , Lectinas Tipo C/genética , Complejo Mayor de Histocompatibilidad , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos , Sistema de Registros , Factor de Transcripción STAT4/genética , Glándulas Salivales Menores , Transactivadores/genética
18.
Front Genet ; 5: 95, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24808905

RESUMEN

Genome-wide association studies (GWAS) are widely applied to identify susceptibility loci for a variety of diseases using genotyping arrays that interrogate known polymorphisms throughout the genome. A particular strength of GWAS is that it is unbiased with respect to specific genomic elements (e.g., coding or regulatory regions of genes), and it has revealed important associations that would have never been suspected based on prior knowledge or assumptions. To date, the discovered SNPs associated with complex human traits tend to have small effect sizes, requiring very large sample sizes to achieve robust statistical power. To address these issues, a number of efficient strategies have emerged for conducting GWAS, including combining study results across multiple studies using meta-analysis, collecting cases through electronic health records, and using samples collected from other studies as controls that have already been genotyped and made publicly available (e.g., through deposition of de-identified data into dbGaP or EGA). In certain scenarios, it may be attractive to use already genotyped controls and divert resources to standardized collection, phenotyping, and genotyping of cases only. This strategy, however, requires that careful attention be paid to the choice of "public controls" and to the comparability of genetic data between cases and the public controls to ensure that any allele frequency differences observed between groups is attributable to locus-specific effects rather than to a systematic bias due to poor matching (population stratification) or differential genotype calling (batch effects). The goal of this paper is to describe some of the potential pitfalls in using previously genotyped control data. We focus on considerations related to the choice of control groups, the use of different genotyping platforms, and approaches to deal with population stratification when cases and controls are genotyped across different platforms.

19.
J Am Heart Assoc ; 1(4): e001420, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23130162

RESUMEN

BACKGROUND: Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied. METHODS AND RESULTS: Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole. CONCLUSIONS: Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole. CLINICAL TRIAL REGISTRATION: URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.).

20.
Atherosclerosis ; 218(2): 344-9, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21726862

RESUMEN

BACKGROUND: Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors. METHODS: IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass. RESULTS: Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a 1mm difference in IMT was associated with a 1.802mm (95% CI: 1.553, 2.051) higher mean IAD. A 1g difference in LV mass was associated with a 0.006mm (95% CI: 0.005, 0.007) higher mean IAD. After adjusting for cardiovascular risk factors and IMT, a 1g difference in LV mass was associated with a 0.006mm (95% CI: 0.005, 0.008) higher mean IAD for women and 0.004mm (95% CI: 0.003, 0.005) higher IAD for men. CONCLUSIONS: Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.


Asunto(s)
Aterosclerosis/patología , Enfermedades Cardiovasculares/diagnóstico , Arteria Carótida Común/patología , Grosor Intima-Media Carotídeo , Tejido Conectivo/patología , Anciano , Aterosclerosis/etnología , Enfermedades Cardiovasculares/metabolismo , Estudios de Cohortes , Etnicidad , Femenino , Ventrículos Cardíacos/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Factores de Riesgo
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