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1.
Cancer Res ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853833

RESUMO

While lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on 9 of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based LOD scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work.

2.
Am J Epidemiol ; 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33861317

RESUMO

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype 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 program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). 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 code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

3.
Genetics ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720349

RESUMO

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence datasets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently amongst the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

5.
Nature ; 586(7831): 763-768, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33057201

RESUMO

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

6.
Stat Appl Genet Mol Biol ; 19(2)2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32374294

RESUMO

Genome wide association study (GWAS) is becoming fundamental in the arduous task of deciphering the etiology of complex diseases. The majority of the statistical models used to address the genes-disease association consider a single response variable. However, it is common for certain diseases to have correlated phenotypes such as in cardiovascular diseases. Usually, GWAS typically sample unrelated individuals from a population and the shared familial risk factors are not investigated. In this paper, we propose to apply a bivariate model using family data that associates two phenotypes with a genetic region. Using generalized estimation equations (GEE), we model two phenotypes, either discrete, continuous or a mixture of them, as a function of genetic variables and other important covariates. We incorporate the kinship relationships into the working matrix extended to a bivariate analysis. The estimation method and the joint gene-set effect in both phenotypes are developed in this work. We also evaluate the proposed methodology with a simulation study and an application to real data.

7.
JAMA Cardiol ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374345

RESUMO

Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, Setting, and Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main Outcomes and Measures: Genetic loci and positional candidate genes associated with SCAD. Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and Relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.

8.
J Obes ; 2020: 9497164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32300485

RESUMO

Importance: Obesity is a worsening epidemic worldwide. Effective and accessible weight loss programs to combat obesity on a large scale are warranted, but a need for frequent face-to-face care might impose a limitation. Objective: To evaluate whether individuals following a weight loss program based on a mobile application, wireless scale, and nutritional program but no face-to-face care can achieve clinically significant weight loss in a large cohort. Design: Retrospective observational analysis. Setting. China from October 2016 to December 2017. Participants. Mobile application users with a minimum of 2 weights (baseline and ≥35 days). Intervention. A commercial (Weijian Technologies) weight loss program consisting of a dietary replacement, self-monitoring using a wireless home scale, and frequent guidance via mobile application. Main Outcome. Mean weight change around 42, 60, 90, and 120 days after program initiation with subgroup analysis by gender, age, and frequency of use. Results: 251,718 individuals, with a mean age of 37.3 years (SD: 9.86) (79% female), were included with a mean weight loss of 4.3 kg (CI: ±0.02) and a mean follow-up of 120 days (SD: 76.8 days). Mean weight loss at 42, 60, 90, and 120 d was 4.1 kg (CI: ±0.02), 4.9 kg (CI: ±0.02), 5.6 kg (CI: ±0.03), and 5.4 kg (CI: ±0.04), respectively. At 120 d, 62.7% of participants had lost at least 5% of their initial weight. Both genders and all usage frequency tertiles showed statistically significant weight loss from baseline at each interval (P < 0.001), and this loss was greater in men than in women (120 d: 6.5 vs. 5.2 kg; P < 0.001). The frequency of recording (categorized as high-, medium-, or low-frequency users) was associated with greater weight loss when comparing high, medium, and low tertile use groups at all time intervals investigated (e.g., 120 d: -8.6, -5.6, and -2.2 kg, respectively; P < 0.001). Conclusions: People following a commercially available hybrid weight loss program using a mobile application, wireless scale, and nutritional program without face-to-face interaction on average achieved clinically significant short- and midterm weight loss. These results support the implementation of comparable technologies for weight control in a large population.

9.
Digit Health ; 6: 2055207620910279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32180992

RESUMO

Introduction: Severe obesity is a growing epidemic that causes significant morbidity and mortality, and is particularly difficult to reverse. Efficacious and cost-effective interventions are needed to combat this epidemic. This study hypothesized that obese people (body mass index (BMI) ≥35 kg/m2) using a remote weight-loss program combining a mobile application, wireless scales, and low-calorie meal replacement would experience clinically significant weight loss. Methods: This study was a retrospective observational analysis of 8275 individuals with a baseline BMI ≥35 kg/m2 who used a remote weight-loss program combining mobile applications, frequent self-weighing, and calorie restriction via meal replacement for a minimum of 35 days. Weight changes were evaluated at multiple intervals (42, 60, 90, and 120 days), and weight loss was evaluated for all and for pre-specified subgroups based on demographic features and frequency of self-weighing. Results: Mean weight loss at 42 days (N = 6781) was 8.1 kg (margin of error (MOE) = 0.126 kg) with 73.6% of users experiencing >5% total body weight loss. Both men (9.1 kg; MOE = 0.172 kg; 7.9% from baseline) and women (7.1 kg; MOE = 0.179 kg; 7.2% from baseline) experienced significant weight loss. At the 120-day interval (N = 2914), mean weight loss was 14 kg (MOE = 0.340 kg), 13% total body weight loss from baseline, and 82.3% of participants had lost >5% of their initial body weight. The decrease in body-fat percent correlated well with weight loss (R = 0.92; p < 0.001). Conclusions: In a large cohort of individuals with class II or III obesity, a remote weight-loss program combining mobile applications, daily self-weighing, and calorie restriction via meal replacement resulted in dramatic weight loss among subjects who were active users when evaluated through a retrospective observational analysis.

10.
Cancer Epidemiol Biomarkers Prev ; 29(2): 434-442, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31826912

RESUMO

BACKGROUND: Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer. METHODS: Parametric genetic linkage analysis was performed on these samples using two distinct analyses-the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. RESULTS: The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3. CONCLUSIONS: Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes. IMPACT: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.

11.
Blood ; 134(19): 1645-1657, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Tromboembolia Venosa/genética , Estudo de Associação Genômica Ampla , Humanos
12.
J Thorac Oncol ; 14(7): 1286-1295, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31078775

RESUMO

INTRODUCTION: Although most patients with SCLC die within a few months of diagnosis, a subgroup of patients survive for many years. Factors determining long-term survivorship remain largely unknown. We present the first comprehensive comparative genomic and tumor microenvironment analyses of SCLC between patients with long-term survivorship and patients with the expected survivorship. METHODS: We compared surgically resected tumors of 23 long-term SCLC survivors (survival >4 years) and 18 SCLC survivors with the expected survival time (survival ≤2 years). There were no significant differences in clinical variables, including TNM staging and curative- versus non-curative-intent surgery between the groups. Gene expression profiling was performed by using microarrays, and tumor microenvironment analyses were performed by immunohistochemistry of prominent immune-related markers. RESULTS: Immune-related genes and pathways represented the majority of the differentially overexpressed genes in long-term survivorship compared with in expected survivorship. The differences in the immunological tumor microenvironment were confirmed by quantitative immunostaining. Increased numbers of tumor-infiltrating and associated lymphocytes were present throughout tumors of long-term survivors of SCLC. Several differentiating patterns of enhanced antitumor immunity were identified. Although some areas of the tumors of long-term survivors of SCLC also harbored higher numbers of suppressive immune cells (monocytes, regulatory lymphocytes, and macrophages), the ratios of these suppressive cells to CD3-positive lymphocytes were generally lower in the tumors of long-term survivors of SCLC, indicating a less tumor-suppressive microenvironment. CONCLUSIONS: Our data demonstrate that long-term survivorship of patients with SCLC is strongly influenced by the presence of the immune cells in the tumor microenvironment. Characterization of the antitumor immune responses may identify opportunities for individualized immunotherapies for SCLC.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Perfilação da Expressão Gênica , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Microambiente Tumoral/imunologia , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida
13.
J Thorac Oncol ; 14(8): 1360-1369, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.


Assuntos
Cromossomos Humanos Par 5 , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Telomerase/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
NPJ Genom Med ; 4: 3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774981

RESUMO

We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes PCSK9, APOB, and LDLR. Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 PCSK9, 730 APOB, and 720 LDLR variants were filtered by imputation quality (r 2 > 0.4), minor allele frequency (>1%), linkage disequilibrium (r 2 < 0.3), and association with LDL-C levels, yielding a set of two PCSK9, three APOB, and five LDLR variants in EA but no variants in AA. Cases and controls were defined for each phecode using the PheWAS package in R. Logistic regression assuming an additive genetic model was used with adjustment for age, sex, and the first two principal components. Significant associations were tested in additional cohorts from Vanderbilt University (n = 29,713), the Marshfield Clinic Personalized Medicine Research Project (n = 9562), and UK Biobank (n = 408,455). We identified one PCSK9, two APOB, and two LDLR variants significantly associated with an examined phecode. Only one of the variants was associated with a non-lipid disease phecode, ("myopia") but this association was not significant in the replication cohorts. In this large-scale PheWAS we did not find LDL-C-related variants in PCSK9, APOB, and LDLR to be associated with non-lipid-related phenotypes including diabetes, neurocognitive disorders, or cataracts.

15.
J Am Coll Cardiol ; 73(1): 58-66, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621952

RESUMO

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.


Assuntos
Anomalias dos Vasos Coronários/epidemiologia , Anomalias dos Vasos Coronários/genética , Endotelina-1/genética , Displasia Fibromuscular/complicações , Loci Gênicos/genética , Proteínas dos Microfilamentos/genética , Doenças Vasculares/congênito , Adulto , Idoso , Austrália , Estudos de Casos e Controles , Anomalias dos Vasos Coronários/complicações , Feminino , Displasia Fibromuscular/genética , França , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Reino Unido , Estados Unidos , Doenças Vasculares/complicações , Doenças Vasculares/epidemiologia , Doenças Vasculares/genética
16.
Genet Epidemiol ; 43(1): 63-81, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30298529

RESUMO

The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).


Assuntos
Registros Eletrônicos de Saúde , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herpes Zoster/genética , Grupo com Ancestrais do Continente Africano/genética , Algoritmos , Cromossomos Humanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Haplótipos/genética , Homozigoto , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal
17.
Menopause ; 25(11): 1275-1285, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30358723

RESUMO

OBJECTIVE: We studied the long-term risk of depressive and anxiety symptoms in women who underwent bilateral oophorectomy before menopause. DESIGN: We conducted a cohort study among all women residing in Olmsted County, MN, who underwent bilateral oophorectomy before the onset of menopause for a noncancer indication from 1950 through 1987. Each member of the bilateral oophorectomy cohort was matched by age with a referent woman from the same population who had not undergone an oophorectomy. In total, we studied 666 women with bilateral oophorectomy and 673 referent women. Women were followed for a median of 24 years, and depressive and anxiety symptoms were assessed using a structured questionnaire via a direct or proxy telephone interview performed from 2001 through 2006. RESULTS: Women who underwent bilateral oophorectomy before the onset of menopause had an increased risk of depressive symptoms diagnosed by a physician (hazard ratio = 1.54, 95% CI: 1.04-2.26, adjusted for age, education, and type of interview) and of anxiety symptoms (adjusted hazard ratio = 2.29, 95% CI: 1.33-3.95) compared with referent women. The findings remained consistent after excluding depressive or anxiety symptoms that first occurred within 10 years after oophorectomy. The associations were greater with younger age at oophorectomy but did not vary across indications for the oophorectomy. In addition, treatment with estrogen to age 50 years in women who underwent bilateral oophorectomy at younger ages did not modify the risk. CONCLUSIONS: Bilateral oophorectomy performed before the onset of menopause is associated with an increased long-term risk of depressive and anxiety symptoms.


Assuntos
Ansiedade/epidemiologia , Ansiedade/etiologia , Depressão/epidemiologia , Depressão/etiologia , Ovariectomia/efeitos adversos , Pré-Menopausa/fisiologia , Adulto , Fatores Etários , Idoso , Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Estrogênios/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Minnesota/epidemiologia , Transtornos Parkinsonianos/diagnóstico , Modelos de Riscos Proporcionais , Risco , Fatores de Risco , Estatísticas não Paramétricas , Inquéritos e Questionários
18.
Blood ; 132(17): 1736, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361463
19.
BMC Genet ; 19(Suppl 1): 81, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30255819

RESUMO

BACKGROUND: GAW20 working group 5 brought together researchers who contributed 7 papers with the aim of evaluating methods to detect genetic by epigenetic interactions. GAW20 distributed real data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, including single-nucleotide polymorphism (SNP) markers, methylation (cytosine-phosphate-guanine [CpG]) markers, and phenotype information on up to 995 individuals. In addition, a simulated data set based on the real data was provided. RESULTS: The 7 contributed papers analyzed these data sets with a number of different statistical methods, including generalized linear mixed models, mediation analysis, machine learning, W-test, and sparsity-inducing regularized regression. These methods generally appeared to perform well. Several papers confirmed a number of causative SNPs in either the large number of simulation sets or the real data on chromosome 11. Findings were also reported for different SNPs, CpG sites, and SNP-CpG site interaction pairs. CONCLUSIONS: In the simulation (200 replications), power appeared generally good for large interaction effects, but smaller effects will require larger studies or consortium collaboration for realizing a sufficient power.


Assuntos
Metilação de DNA , Estudo de Associação Genômica Ampla , Ilhas de CpG , Genótipo , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/genética , Hipoglicemiantes/uso terapêutico , Aprendizado de Máquina , Polimorfismo de Nucleotídeo Único
20.
BMC Proc ; 12(Suppl 9): 26, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30263042

RESUMO

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication.

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