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BACKGROUND: The association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations. METHODS: Using X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case-control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses. RESULTS: Among 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC ([Formula: see text] 0.020, SE 0.004, p 4.97 × 10-08), with suggestive evidence of association with FEV1 ([Formula: see text] 0.092, SE 0.018, p 3.40 × 10-07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions. CONCLUSIONS: This investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology. Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease.
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Enfisema , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Femenino , Masculino , Humanos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Fenotipo , Cromosoma XRESUMEN
SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome-wide association studies (GWAS), we looked at the association between whole-genome sequencing (WGS) data of the virus and COVID-19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single-stranded SARS-CoV-2 genomes of COVID-19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome-wide significance (p values of 4.09e-09 and 4.41e-23, respectively), though only 25,088 bp remained significant in follow-up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e-13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow-up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real-time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.
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COVID-19 , Glicoproteína de la Espiga del Coronavirus , Brasil , Estudio de Asociación del Genoma Completo , Humanos , Mutación , Filogenia , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
MOTIVATION: Analysis of rare variants in family-based studies remains a challenge. Transmission-based approaches provide robustness against population stratification, but the evaluation of the significance of test statistics based on asymptotic theory can be imprecise. Also, power will depend heavily on the choice of the test statistic and on the underlying genetic architecture of the locus, which will be generally unknown. RESULTS: In our proposed framework, we utilize the FBAT haplotype algorithm to obtain the conditional offspring genotype distribution under the null hypothesis given the sufficient statistic. Based on this conditional offspring genotype distribution, the significance of virtually any association test statistic can be evaluated based on simulations or exact computations, without the need for asymptotic approximations. Besides standard linear burden-type statistics, this enables our approach to also evaluate other test statistics such as variance components statistics, higher criticism approaches, and maximum-single-variant-statistics, where asymptotic theory might be involved or does not provide accurate approximations for rare variant data. Based on these P-values, combined test statistics such as the aggregated Cauchy association test (ACAT) can also be utilized. In simulation studies, we show that our framework outperforms existing approaches for family-based studies in several scenarios. We also applied our methodology to a TOPMed whole-genome sequencing dataset with 897 asthmatic trios from Costa Rica. AVAILABILITY AND IMPLEMENTATION: FBAT software is available at https://sites.google.com/view/fbatwebpage. Simulation code is available at https://github.com/julianhecker/FBAT_rare_variant_test_simulations. Whole-genome sequencing data for 'NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica' is available at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000988.v4.p1. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Whole-exome sequencing using family data has identified rare coding variants in Mendelian diseases or complex diseases with Mendelian subtypes, using filters based on variant novelty, functionality, and segregation with the phenotype within families. However, formal statistical approaches are limited. We propose a gene-based segregation test (GESE) that quantifies the uncertainty of the filtering approach. It is constructed using the probability of segregation events under the null hypothesis of Mendelian transmission. This test takes into account different degrees of relatedness in families, the number of functional rare variants in the gene, and their minor allele frequencies in the corresponding population. In addition, a weighted version of this test allows incorporating additional subject phenotypes to improve statistical power. We show via simulations that the GESE and weighted GESE tests maintain appropriate type I error rate, and have greater power than several commonly used region-based methods. We apply our method to whole-exome sequencing data from 49 extended pedigrees with severe, early-onset chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD study (BEOCOPD) and identify several promising candidate genes. Our proposed methods show great potential for identifying rare coding variants of large effect and high penetrance for family-based sequencing data. The proposed tests are implemented in an R package that is available on CRAN (https://cran.r-project.org/web/packages/GESE/).
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Variación Genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Análisis de Secuencia de ADN/métodos , Edad de Inicio , Boston , Simulación por Computador , Bases de Datos Genéticas , Familia , Genoma Humano , Humanos , Modelos Genéticos , Penetrancia , Estándares de ReferenciaRESUMEN
RATIONALE: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. OBJECTIVES: To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers. METHODS: A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. MEASUREMENTS AND MAIN RESULTS: We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. CONCLUSIONS: This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic approaches in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
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Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Enfisema Pulmonar/genética , Estudios de Cohortes , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Enfisema Pulmonar/diagnóstico por imagen , Enfisema Pulmonar/fisiopatología , Fumar/fisiopatología , Tomografía Computarizada por Rayos XRESUMEN
RATIONALE: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES: To identify coding variants associated with COPD. METHODS: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.
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Exoma/genética , Predisposición Genética a la Enfermedad/genética , Interleucina-27/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Adulto , Anciano , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). RESULTS: Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)). CONCLUSIONS: In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.
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Población Negra/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Fumar/genética , Población Blanca/genética , Broncodilatadores/farmacología , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 4/genética , Estudios de Cohortes , Femenino , Volumen Espiratorio Forzado , Genoma Humano , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Factores de Riesgo , EspirometríaRESUMEN
RATIONALE: Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes. OBJECTIVES: To identify genetic determinants of quantitative imaging phenotypes. METHODS: We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD. MEASUREMENTS AND MAIN RESULTS: The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes. CONCLUSIONS: Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD and also identify imaging features associated with previously identified lung function loci.
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Pulmón/diagnóstico por imagen , Enfisema Pulmonar/genética , Anciano , Proteínas Portadoras/genética , Estudios de Cohortes , Femenino , Proteínas Activadoras de GTPasa/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Procesamiento de Imagen Asistido por Computador , Proteína 2 Reguladora de Hierro/genética , Estudios Longitudinales , Masculino , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfisema Pulmonar/diagnóstico por imagen , Receptor para Productos Finales de Glicación Avanzada/genética , Receptores Nicotínicos/genética , Serpinas/genética , Tomografía Computarizada por Rayos X , Proteínas Supresoras de Tumor/genéticaRESUMEN
Many correlated disease variables are analyzed jointly in genetic studies in the hope of increasing power to detect causal genetic variants. One approach involves assessing the relationship between each phenotype and each SNP individually and using a Bonferroni correction for the effective number of tests conducted. Alternatively, one can apply a multivariate regression or a dimension reduction technique, such as principal component analysis, and test for the association with the principal components of the phenotypes rather than the individual phenotypes. Inspired by the previous approaches of combining phenotypes to maximize heritability at individual SNPs, in this paper, we propose to construct a maximally heritable (MaxH) phenotype by taking advantage of the estimated total heritability and co-heritability. The heritability and co-heritability only need to be estimated once; therefore, our method is applicable to genome-wide scans. The MaxH phenotype is a linear combination of the individual phenotypes with increased heritability and power over the phenotypes being combined. Simulations show that the heritability and power achieved agree well with the theory for large samples and two phenotypes. We compare our approach with commonly used methods and assess both the heritability and the power of the MaxH phenotype. Moreover, we provide suggestions for how to choose the phenotypes for combination. An application of our approach to a GWAS on chronic obstructive pulmonary disease shows its practical relevance.
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Modelos Genéticos , Fenotipo , Estudio de Asociación del Genoma Completo , Humanos , Enfermedad Pulmonar Obstructiva Crónica/genéticaRESUMEN
The revolution in next-generation sequencing has made obtaining both common and rare high-quality sequence variants across the entire genome feasible. Because researchers are now faced with the analytical challenges of handling a massive amount of genetic variant information from sequencing studies, numerous methods have been developed to assess the impact of both common and rare variants on disease traits. In this report, whole genome sequencing data from Genetic Analysis Workshop 18 was used to compare the power of several methods, considering both family-based and population-based designs, to detect association with variants in the MAP4 gene region and on chromosome 3 with blood pressure. To prioritize variants across the genome for testing, variants were first functionally assessed using prediction algorithms and expression quantitative trait loci (eQTLs) data. Four set-based tests in the family-based association tests (FBAT) framework--FBAT-v, FBAT-lmm, FBAT-m, and FBAT-l--were used to analyze 20 pedigrees, and 2 variance component tests, sequence kernel association test (SKAT) and genome-wide complex trait analysis (GCTA), were used with 142 unrelated individuals in the sample. Both set-based and variance-component-based tests had high power and an adequate type I error rate. Of the various FBATs, FBAT-l demonstrated superior performance, indicating the potential for it to be used in rare-variant analysis. The updated FBAT package is available at: http://www.hsph.harvard.edu/fbat/.
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BACKGROUND: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. METHODS: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5â×â10(-7) in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5â×â10(-8)). FINDINGS: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38â×â10(-14)), FAM13A (p=1·12â×â10(-14)), and HHIP (p=1·57â×â10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25â×â10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4â×â10(-9)). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6â×â10(-9)) and TGFB2 (overall joint meta-analysis p=8·3â×â10(-9)). INTERPRETATION: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. FUNDING: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.
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Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
RATIONALE: Previous studies of chronic obstructive pulmonary disease (COPD) have suggested that genetic factors play an important role in the development of disease. However, single-nucleotide polymorphisms that are associated with COPD in genome-wide association studies have been shown to account for only a small percentage of the genetic variance in phenotypes of COPD, such as spirometry and imaging variables. These phenotypes are highly predictive of disease, and family studies have shown that spirometric phenotypes are heritable. OBJECTIVES: To assess the heritability and coheritability of four major COPD-related phenotypes (measurements of FEV1, FEV1/FVC, percent emphysema, and percent gas trapping), and COPD affection status in smokers of non-Hispanic white and African American descent using a population design. METHODS: Single-nucleotide polymorphisms from genome-wide association studies chips were used to calculate the relatedness of pairs of individuals and a mixed model was adopted to estimate genetic variance and covariance. MEASUREMENTS AND MAIN RESULTS: In the non-Hispanic whites, estimated heritabilities of FEV1 and FEV1/FVC were both about 37%, consistent with estimates in the literature from family-based studies. For chest computed tomography scan phenotypes, estimated heritabilities were both close to 25%. Heritability of COPD affection status was estimated as 37.7% in both populations. CONCLUSIONS: This study suggests that a large portion of the genetic risk of COPD is yet to be discovered and gives rationale for additional genetic studies of COPD. The estimates of coheritability (genetic covariance) for pairs of the phenotypes suggest considerable overlap of causal genetic loci.
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Enfermedad Pulmonar Obstructiva Crónica/genética , Fumar/efectos adversos , Femenino , Volumen Espiratorio Forzado/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Grupos Raciales/genética , Fumar/fisiopatología , Capacidad Vital/genéticaRESUMEN
BACKGROUND: We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF(25-75)) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566). METHODS: 257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches. RESULTS: The change in FEF(25-75) per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was -91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF(25-75) of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake. CONCLUSIONS: Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function.
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Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Asma/genética , Suplementos Dietéticos , Exposición a Riesgos Ambientales/efectos adversos , Enzimas/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Ozono/efectos adversos , Factores de Edad , Deficiencia de Ácido Ascórbico/tratamiento farmacológico , Deficiencia de Ácido Ascórbico/epidemiología , Asma/diagnóstico , Asma/enzimología , Asma/epidemiología , Asma/fisiopatología , Asma/prevención & control , Niño , Estudios de Cohortes , Método Doble Ciego , Femenino , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Humanos , Modelos Lineales , Pulmón/fisiopatología , Masculino , Flujo Espiratorio Medio Máximo , México/epidemiología , NAD(P)H Deshidrogenasa (Quinona)/genética , Fenotipo , Polimorfismo Genético , Medición de Riesgo , Factores de Riesgo , Salud UrbanaRESUMEN
OBJECTIVE: Anorexia nervosa and bulimia nervosa (BN) are rare, but eating disorders not otherwise specified (EDNOS) are relatively common among female participants. Our objective was to evaluate whether BN and subtypes of EDNOS are predictive of developing adverse outcomes. METHODS: This study comprised a prospective analysis of 8594 female participants from the ongoing Growing Up Today Study. Questionnaires were sent annually from 1996 through 2001, then biennially through 2007 and 2008. Participants who were 9 to 15 years of age in 1996 and completed at least 2 consecutive questionnaires between 1996 and 2008 were included in the analyses. Participants were classified as having BN (≥ weekly binge eating and purging), binge eating disorder (BED; ≥ weekly binge eating, infrequent purging), purging disorder (PD; ≥ weekly purging, infrequent binge eating), other EDNOS (binge eating and/or purging monthly), or nondisordered. RESULTS: BN affected â¼1% of adolescent girls; 2% to 3% had PD and another 2% to 3% had BED. Girls with BED were almost twice as likely as their nondisordered peers to become overweight or obese (odds ratio [OR]: 1.9 [95% confidence interval: 1.0-3.5]) or develop high depressive symptoms (OR: 2.3 [95% confidence interval: 1.0-5.0]). Female participants with PD had a significantly increased risk of starting to use drugs (OR: 1.7) and starting to binge drink frequently (OR: 1.8). CONCLUSIONS: PD and BED are common and predict a range of adverse outcomes. Primary care clinicians should be made aware of these disorders, which may be underrepresented in eating disorder clinic samples. Efforts to prevent eating disorders should focus on cases of subthreshold severity.
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Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Resultado del Tratamiento , Adolescente , Trastornos Relacionados con Alcohol/epidemiología , Trastornos Relacionados con Alcohol/psicología , Anorexia Nerviosa/epidemiología , Anorexia Nerviosa/terapia , Trastorno por Atracón/epidemiología , Trastorno por Atracón/terapia , Peso Corporal , Bulimia Nerviosa/epidemiología , Bulimia Nerviosa/terapia , Niño , Estudios Transversales , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Femenino , Humanos , Obesidad/epidemiología , Obesidad/psicología , Sobrepeso/epidemiología , Sobrepeso/psicología , Estudios Prospectivos , Riesgo , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/psicología , Estados UnidosRESUMEN
Identifying population stratification and genotyping error are important for candidate gene association studies using the Transmission Disequilibrium Test (TDT). Although the TDT retains the prespecified Type I error in the presence of population stratification, the test may have decreased power in the presence of population stratification. Genotyping error can also cause the TDT to have an elevated Type I error. Differentiating population stratification from genotyping error remains a challenge for geneticists. Both genotyping error and population stratification can result in an increase in the observed homozygosity of a sample relative to that expected assuming Hardy-Weinberg Equilibrium (HWE). We show that when family data are available, even if a limited number of markers are genotyped, evaluating the markers that show statistically significant deviation from HWE with the Mating Type Distortion Test (MTDT)--a test based on the mating type distribution--can reliably differentiate genotyping error from population stratification. We simulate data based on several models of genotyping error in previously published literature, and show how this method could be used in practice to assist in differentiating population stratification from systematic genotyping error.
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Técnicas Genéticas , Técnicas de Genotipaje , Familia , Estudio de Asociación del Genoma Completo , Homocigoto , Humanos , Desequilibrio de Ligamiento , Modelos GenéticosRESUMEN
In clinical trials multiple outcomes are often used to assess treatment interventions. This paper presents an evaluation of likelihood-based methods for jointly testing treatment effects in clinical trials with multiple continuous outcomes. Specifically, we compare the power of joint tests of treatment effects obtained from joint models for the multiple outcomes with univariate tests based on modeling the outcomes separately. We also consider the power and bias of tests when data are missing, a common feature of many trials, especially in psychiatry. Our results suggest that joint tests capitalize on the correlation of multiple outcomes and are more powerful than standard univariate methods, especially when outcomes are missing completely at random. When outcomes are missing at random, test procedures based on correctly specified joint models are unbiased, while standard univariate procedures are not. Results of a simulation study are reported, and the methods are illustrated in an example from the Clinical Antipsychotic Trials of Intervention Effectiveness for schizophrenia.
Asunto(s)
Bioestadística/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Resultado del Tratamiento , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Ensayos Clínicos como Asunto/estadística & datos numéricos , Dibenzotiazepinas/efectos adversos , Dibenzotiazepinas/uso terapéutico , Humanos , Funciones de Verosimilitud , Modelos Lineales , Síndrome Metabólico/etiología , Modelos Estadísticos , Análisis Multivariante , Perfenazina/efectos adversos , Perfenazina/uso terapéutico , Fumarato de Quetiapina , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Esquizofrenia/tratamiento farmacológicoRESUMEN
Investigators sometimes use information obtained from multiple informants about a given variable. We focus on estimating the effect of a predictor on a continuous outcome, when that (true) predictor cannot be observed directly but is measured by 2 informants. We describe various approaches to using information from 2 informants to estimate a regression or correlation coefficient for the effect of the (true) predictor on the outcome. These approaches include methods we refer to as single informant, simple average, optimal weighted average, principal components analysis, and classical measurement error. Each of these 5 methods effectively uses a weighted average of the informants' reports as a proxy for the true predictor in calculating the correlation or regression coefficient. We compare the performance of these methods in simulation experiments that assume a rounded congeneric measurement model for the relationship between the informants' reports and a true predictor that is a mixture of zeros and positively distributed continuous values. We also compare the methods' performance in a real data example-the relationship between vigorous physical activity (the predictor) and body mass index (the continuous outcome). The results of the simulations and the example suggest that the simple average is a reasonable choice when there are only 2 informants.
Asunto(s)
Índice de Masa Corporal , Actividad Motora/fisiología , Obesidad/epidemiología , Valor Predictivo de las Pruebas , Ejercicio Físico/fisiología , Femenino , Humanos , Modelos Lineales , Masculino , Modelos EstadísticosRESUMEN
It is useful to have robust gene-environment interaction tests that can utilize a variety of family structures in an efficient way. This article focuses on tests for gene-environment interaction in the presence of main genetic and environmental effects. The objective is to develop powerful tests that can combine trio data with parental genotypes and discordant sibships when parents' genotypes are missing. We first make a modest improvement on a method for discordant sibs (discordant on phenotype), but the approach does not allow one to use families when all offspring are affected, e.g., trios. We then make a modest improvement on a Mendelian transmission-based approach that is inefficient when discordant sibs are available, but can be applied to any nuclear family. Finally, we propose a hybrid approach that utilizes the most efficient method for a specific family type, then combines over families. We utilize this hybrid approach to analyze a chronic obstructive pulmonary disorder dataset to test for gene-environment interaction in the Serpine2 gene with smoking. The methods are freely available in the R package fbati.
Asunto(s)
Interacción Gen-Ambiente , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Modelos Genéticos , Núcleo Familiar , Serpina E2/genética , Fumar/genética , Simulación por Computador , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Metagenómica/métodos , Fumar/epidemiologíaRESUMEN
Rapid advances in sequencing technologies set the stage for the large-scale medical sequencing efforts to be performed in the near future, with the goal of assessing the importance of rare variants in complex diseases. The discovery of new disease susceptibility genes requires powerful statistical methods for rare variant analysis. The low frequency and the expected large number of such variants pose great difficulties for the analysis of these data. We propose here a robust and powerful testing strategy to study the role rare variants may play in affecting susceptibility to complex traits. The strategy is based on assessing whether rare variants in a genetic region collectively occur at significantly higher frequencies in cases compared with controls (or vice versa). A main feature of the proposed methodology is that, although it is an overall test assessing a possibly large number of rare variants simultaneously, the disease variants can be both protective and risk variants, with moderate decreases in statistical power when both types of variants are present. Using simulations, we show that this approach can be powerful under complex and general disease models, as well as in larger genetic regions where the proportion of disease susceptibility variants may be small. Comparisons with previously published tests on simulated data show that the proposed approach can have better power than the existing methods. An application to a recently published study on Type-1 Diabetes finds rare variants in gene IFIH1 to be protective against Type-1 Diabetes.