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1.
Nature ; 622(7982): 329-338, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37794186

RESUMEN

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.


Asunto(s)
Bancos de Muestras Biológicas , Proteínas Sanguíneas , Bases de Datos Factuales , Genómica , Salud , Proteoma , Proteómica , Humanos , Sistema del Grupo Sanguíneo ABO/genética , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/genética , COVID-19/genética , Descubrimiento de Drogas , Epistasis Genética , Fucosiltransferasas/metabolismo , Predisposición Genética a la Enfermedad , Plasma/química , Proproteína Convertasa 9/metabolismo , Proteoma/análisis , Proteoma/genética , Asociación entre el Sector Público-Privado , Sitios de Carácter Cuantitativo , Reino Unido , Galactósido 2-alfa-L-Fucosiltransferasa
2.
Am J Hum Genet ; 108(7): 1350-1355, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34115965

RESUMEN

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.


Asunto(s)
COVID-19/diagnóstico , COVID-19/genética , Secuenciación del Exoma , Exoma/genética , Predisposición Genética a la Enfermedad , Hospitalización/estadística & datos numéricos , COVID-19/inmunología , COVID-19/terapia , Femenino , Humanos , Interferones/genética , Masculino , Pronóstico , SARS-CoV-2 , Tamaño de la Muestra
3.
Blood ; 133(25): 2651-2663, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-30923040

RESUMEN

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.


Asunto(s)
Proteínas Hedgehog/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteína con Dedos de Zinc GLI1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Regulación Leucémica de la Expresión Génica/genética , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Piridinas/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
4.
Blood ; 134(19): 1645-1657, 2019 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-31420334

RESUMEN

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Tromboembolia Venosa/genética , Estudio de Asociación del Genoma Completo , Humanos
5.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30659681

RESUMEN

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Asunto(s)
Exoma/genética , Estudio de Asociación del Genoma Completo/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis por Micromatrices/métodos , Tromboembolia Venosa/genética , Negro o Afroamericano/genética , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/estadística & datos numéricos , Humanos , Masculino , Análisis por Micromatrices/estadística & datos numéricos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Tamaño de la Muestra , Tromboembolia Venosa/etnología
6.
Haematologica ; 105(7): 1963-1968, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31582554

RESUMEN

Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for VTE according to categories of cancer and FGG In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2-2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two-fold (HR 2.0, 95% CI: 1.1-3.6) higher risk of VTE than cancer patients without the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5-11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3-4.7) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02-3.21, attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE.


Asunto(s)
Fibrinógeno/genética , Neoplasias , Tromboembolia Venosa , Alelos , Humanos , Incidencia , Neoplasias/genética , Factores de Riesgo , Tromboembolia Venosa/etiología , Tromboembolia Venosa/genética
7.
Hum Mol Genet ; 25(19): 4350-4368, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27577874

RESUMEN

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.


Asunto(s)
Enfermedades Cardiovasculares/genética , Estudio de Asociación del Genoma Completo , Ventrículos Cardíacos/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.5/genética , Negro o Afroamericano/genética , Alelos , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Electrocardiografía , Femenino , Genotipo , Humanos , Masculino , Miocardio/patología , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética
9.
BMC Bioinformatics ; 18(1): 207, 2017 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-28388874

RESUMEN

BACKGROUND: Genomic interaction studies use next-generation sequencing (NGS) to examine the interactions between two loci on the genome, with subsequent bioinformatics analyses typically including annotation, intersection, and merging of data from multiple experiments. While many file types and analysis tools exist for storing and manipulating single locus NGS data, there is currently no file standard or analysis tool suite for manipulating and storing paired-genomic-loci: the data type resulting from "genomic interaction" studies. As genomic interaction sequencing data are becoming prevalent, a standard file format and tools for working with these data conveniently and efficiently are needed. RESULTS: This article details a file standard and novel software tool suite for working with paired-genomic-loci data. We present the paired-genomic-loci (PGL) file standard for genomic-interactions data, and the accompanying analysis tool suite "pgltools": a cross platform, pypy compatible python package available both as an easy-to-use UNIX package, and as a python module, for integration into pipelines of paired-genomic-loci analyses. CONCLUSIONS: Pgltools is a freely available, open source tool suite for manipulating paired-genomic-loci data. Source code, an in-depth manual, and a tutorial are available publicly at www.github.com/billgreenwald/pgltools , and a python module of the operations can be installed from PyPI via the PyGLtools module.


Asunto(s)
Cromatina/metabolismo , Genómica/métodos , Programas Informáticos , Cromatina/genética , Inmunoprecipitación de Cromatina , Sitios Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento
10.
Hum Genet ; 136(7): 897-902, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28528403

RESUMEN

Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10-6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.


Asunto(s)
Análisis de la Aleatorización Mendeliana , Obesidad/genética , Tromboembolia Venosa/genética , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Modelos Logísticos , Masculino , Obesidad/complicaciones , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Tromboembolia Venosa/complicaciones , Población Blanca
11.
Am J Hum Genet ; 94(3): 349-60, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24560520

RESUMEN

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.


Asunto(s)
Presión Sanguínea , Diástole , Genética de Población , Sístole , Población Blanca/genética , Presión Arterial , Biología Computacional/métodos , Europa (Continente) , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple , Control de Calidad , Sitios de Carácter Cuantitativo , Factores de Riesgo
12.
Cultur Divers Ethnic Minor Psychol ; 23(2): 300-309, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27454887

RESUMEN

OBJECTIVES: It is imperative that individual differences in the cultural contexts of adolescent mothers, whose parenting is often linked to poor child outcomes, be better understood, especially among Puerto Rican-origin mothers who experience high rates of poverty. Behaviors that mothers use to elicit compliance from their children are important to investigate, because children's ability to engage in regulated, compliant behavior has long-term consequences for their adjustment. This study tested whether mothers' orientation to both American and Latino cultures influenced the associations between such maternal behaviors and compliant and defiant child behaviors. METHOD: The sample included 123 young, Puerto Rican-origin mothers and their 24-month-old toddlers. Behaviors coded from a toy cleanup task measured maternal guidance and control and child compliance and defiance, and acculturation and enculturation were measured with a self-report questionnaire. RESULTS: Maternal guidance predicted more child compliance, with no significant variations by cultural orientation; however, mothers who were more enculturated had children who were more compliant. As predicted, mothers' more frequent use of control was related to more child defiance for mothers reporting high levels of acculturation, and not for less acculturated mothers. CONCLUSIONS: Findings support the hypothesis that individual differences in cultural orientation influence variations in associations between certain maternal and child behaviors. (PsycINFO Database Record


Asunto(s)
Conducta Infantil/psicología , Madres/psicología , Responsabilidad Parental/etnología , Aculturación , Adolescente , Conducta Infantil/etnología , Preescolar , Femenino , Humanos , Masculino , Relaciones Madre-Hijo , Responsabilidad Parental/psicología , Pobreza , Puerto Rico/etnología , Encuestas y Cuestionarios
13.
Blood ; 124(1): 84-95, 2014 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-24787006

RESUMEN

We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Factores de Transcripción Forkhead/biosíntesis , Regulación Leucémica de la Expresión Génica/genética , Leucemia Linfocítica Crónica de Células B/genética , MicroARNs/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Proteínas Represoras/biosíntesis , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Interferente Pequeño , Receptores de Antígenos de Linfocitos B/genética , Proteínas Represoras/genética , Transducción de Señal/fisiología , Transfección
14.
Haematologica ; 101(9): 1046-53, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27479824

RESUMEN

Venous thromboembolism occurs frequently in cancer patients. Two variants in the factor 5 gene (F5), rs6025 encoding for the factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with venous thromboembolism. We assessed the joint effect of active cancer and these two F5 variants on venous thromboembolism risk in a case-cohort study. Cases with a first venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromsø, Norway. Venous thromboembolism was classified as cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of cancer. Active cancer was associated with an 8.9-fold higher risk of venous thromboembolism (95% CI 7.2-10.9). The risk of cancer-related venous thromboembolism was 16.7-fold (95% CI 9.9-28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active cancer. In subjects with active cancer the risk of venous thromboembolism was 15.9-fold higher (95% CI 9.1-27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4-35.8) higher in those with two risk alleles compared with non-carriers without active cancer. A synergistic interaction was observed between active cancer and factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5-14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5-29.2). The incidence of venous thromboembolism during the initial 6 months following a diagnosis of cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of cancer and F5 variants synergistically increases venous thromboembolism risk.


Asunto(s)
Factor V/genética , Variación Genética , Neoplasias/complicaciones , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Modelos de Riesgos Proporcionales , Riesgo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/mortalidad
15.
Hum Mol Genet ; 22(8): 1663-78, 2013 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-23303523

RESUMEN

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.


Asunto(s)
Presión Sanguínea/genética , Enfermedades Cardiovasculares/genética , Mapeo Cromosómico , Estudio de Asociación del Genoma Completo , Adulto , Anciano , Enfermedades Cardiovasculares/fisiopatología , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genética
16.
Hum Mol Genet ; 22(16): 3329-46, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23599027

RESUMEN

African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.


Asunto(s)
Negro o Afroamericano/genética , Estudio de Asociación del Genoma Completo , Menarquia/genética , Adolescente , Estudios de Casos y Controles , Niño , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Femenino , Sitios Genéticos , Variación Genética , Humanos , Modelos Lineales , Glicoproteínas de Membrana , Proteínas de la Membrana/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca/genética , Adulto Joven
17.
Am J Hum Genet ; 91(5): 823-38, 2012 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-23063622

RESUMEN

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.


Asunto(s)
Estudio de Asociación del Genoma Completo , Lípidos/genética , Sitios de Carácter Cuantitativo , HDL-Colesterol/sangre , HDL-Colesterol/genética , LDL-Colesterol/sangre , LDL-Colesterol/genética , Femenino , Genotipo , Humanos , Lípidos/sangre , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Factores Sexuales , Triglicéridos/sangre , Triglicéridos/genética , Población Blanca
18.
Genet Med ; 17(8): 660-7, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25356967

RESUMEN

PURPOSE: 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD. METHODS: We performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases. RESULTS: We determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD. CONCLUSION: Our study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes.Genet Med 17 8, 660-667.


Asunto(s)
Ligasas de Carbono-Carbono/deficiencia , Consanguinidad , Trastornos Innatos del Ciclo de la Urea/genética , Adulto , Alelos , Ligasas de Carbono-Carbono/genética , Estudios de Casos y Controles , Exoma , Femenino , Estudios de Asociación Genética , Homocigoto , Humanos , Recién Nacido , Masculino , Mutación , Tamizaje Neonatal , Trastornos Innatos del Ciclo de la Urea/enzimología
19.
BMC Bioinformatics ; 15: 125, 2014 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-24884706

RESUMEN

BACKGROUND: Genotypes generated in next generation sequencing studies contain errors which can significantly impact the power to detect signals in common and rare variant association tests. These genotyping errors are not explicitly filtered by the standard GATK Variant Quality Score Recalibration (VQSR) tool and thus remain a source of errors in whole exome sequencing (WES) projects that follow GATK's recommended best practices. Therefore, additional data filtering methods are required to effectively remove these errors before performing association analyses with complex phenotypes. Here we empirically derive thresholds for genotype and variant filters that, when used in conjunction with the VQSR tool, achieve higher data quality than when using VQSR alone. RESULTS: The detailed filtering strategies improve the concordance of sequenced genotypes with array genotypes from 99.33% to 99.77%; improve the percent of discordant genotypes removed from 10.5% to 69.5%; and improve the Ti/Tv ratio from 2.63 to 2.75. We also demonstrate that managing batch effects by separating samples based on different target capture and sequencing chemistry protocols results in a final data set containing 40.9% more high-quality variants. In addition, imputation is an important component of WES studies and is used to estimate common variant genotypes to generate additional markers for association analyses. As such, we demonstrate filtering methods for imputed data that improve genotype concordance from 79.3% to 99.8% while removing 99.5% of discordant genotypes. CONCLUSIONS: The described filtering methods are advantageous for large population-based WES studies designed to identify common and rare variation associated with complex diseases. Compared to data processed through standard practices, these strategies result in substantially higher quality data for common and rare association analyses.


Asunto(s)
Exoma , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de Secuencia de ADN/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/normas
20.
Am J Hum Genet ; 88(1): 6-18, 2011 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-21194676

RESUMEN

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.


Asunto(s)
Estatura/genética , Sistema Cardiovascular , Heterogeneidad Genética , Sitios Genéticos , Polimorfismo de Nucleótido Simple , Adulto , Negro o Afroamericano/genética , Pueblo Asiatico/genética , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Humanos , Interleucina-11/genética , Masculino , Proteína smad3/genética , Población Blanca/genética
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