14390 results for ""Pennsylvania+German"+ACS+study+'Socius'+open+access"

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• Genetics of Mammographic Density in Ashkenazi Jews

  Mammographic density (MD) is a strong risk factor for breast cancer and is also a highly heritable trait with ~60-70% of the variance due to genetic factors, based on twin studies. MD is also higher in families with a strong history of breast cancer. Genome-wide association studies (GWAS), which focus on common genetic variants, have identified several single nucleotide polymorphisms (SNPs) associated with MD. However, these SNPs explain a very small fraction of the variance of MD, suggesting many other genes are involved. Thus, the vast majority of the heritability of mammographic density remains unexplained and may be explained, at least in part, by rare variants. Ashkenazi Jewish women are a founder population; founder populations frequently have alleles affecting phenotypes which may be unique and/or extremely rare in other populations. Prior reports have identified an association between higher mammographic density and Ashkenazi Jewish ancestry. Therefore, we developed a study of mammographic density in AJ women. We combined datasets from several different cohorts including (a) the California Pacific Medical Center Research Institute (b) the Athena Breast Health Cohort and (c) the Marin Women's study. In each study, we identified women who reported AJ ancestry (determined by self-report or by genetic analysis). We identified mammograms by linking the women to the San Francisco Mammography Registry. We retrieved digital mammographic results and used software to infer volumetric density and percent volumetric density for each woman. We then performed genome-wide genotyping of the samples using the Illumina MEGA array.

  Study phs001857

• Population Architecture using Genomics and Epidemiology (PAGE): Causal Variants Across the Life Course (CALiCo): Atherosclerosis Risk in Communities (ARIC)

  CALiCo ARIC The Atherosclerosis Risk in Communities Study (ARIC), sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes a Cohort Component and a Community Surveillance Component. Cohort enrollment began in 1987. Each ARIC field center randomly selected and recruited a sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam wastook place in 1996-98. Follow-up occurs yearly byA fifth cohort examination is underway (2011-2013). Yearly telephone tointerviews maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. The study conducts community surveillance of inpatient heart failure (ages 55 years and older) and cohort surveillance outpatient heart failure events beginning in 2005.

  Study phs000223

• DNA Methylomic Profiling of Preeclampsia Across Pregnancy

  Preeclampsia (PE) is a hypertensive, multi-system disorder of pregnancy that significantly impacts maternal and infant morbidity/mortality across the globe, as it increases risk of cardiovascular disease and remains a leading killer of women and babies. Despite PE's significant impact on morbidity/mortality, there are no clinically reliable biomarkers that predict PE. DNA methylation, a dynamic regulator of gene expression, represents a mechanism that is known to be impacted by the environment. Because PE stems from a dysfunctional placenta that releases debris into the maternal circulation, we hypothesized that the in-vivo environment created by the dysfunctional placenta will impact DNA methylation in the maternal circulation, and that these blood-based methylation profiles would serve as a systemic biomarker of the maternal response to placental dysfunction. Our overall objective of this pilot study was to longitudinally characterize DNA methylation profiles across the three trimesters of pregnancy in the maternal blood at time points before and after clinically overt PE using a targeted (endoglin and endoglin-related genes) and a discovery-based approach. For this pilot study, 28 normotensive control participants and 28 PE case participants enrolled in the NICHD funded pregnancy study entitled Prenatal Exposures and Preeclampsia Prevention: Mechanisms of Preeclampsia and the Impact of Obesity (PEPP3; P01HD30367) were 1:1 frequency matched on self-reported race, pre-pregnancy BMI, smoking history, and gestational age at sample collection. Methylation data were collected with the Infinium® MethylationEPIC Beadchip. Methylation assay data collection were carried out at Johns Hopkins University Genetic Resources Core Facility, The SNP Center, Baltimore, MD, USA.

  Study phs001937

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Victorian Collaborative AuTism Study (CATS): Family and Community Study of the Genetics of Autism Spectrum Disorder

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002044

• Norepinephrine Transporter Blockade as a Pathophysiological Biomarker in Neurogenic Orthostatic Hypotension

  The clinical picture of autonomic failure is dominated by disabling orthostatic hypotension. Recent developments in the understanding of the underlying pathophysiology of the discrete clinical forms of autonomic failure have revealed that participants with multiple system atrophy (MSA) are characterized by impairment of central autonomic pathways crucial for autonomic cardiovascular control, but have intact peripheral postganglionic noradrenergic fibers. Participants with MSA have peripheral residual sympathetic tone that is no longer modulated by central autonomic centers and is not under baroreflex control and, therefore, cannot be harnessed to improve their orthostatic hypotension. On the other hand, participants with pure autonomic failure (PAF) and with Parkinson' s disease (PD) are characterized by neurodegeneration and loss of peripheral noradrenergic fibers, as evidenced by low levels of plasma norepinephrine and absent cardiac uptake of labeled catechols. Pharmacological inhibition of the norepinephrine transporter (NET) is an example of an approach that can take advantage of the participants' own residual sympathetic tone. NET inhibition will increase synaptic norepinephrine that is tonically released in MSA participants by preventing its reuptake. This should result in an increase in blood pressure. This is a longitudinal study of 50 participants, age 18-80 years with neurogenic orthostatic hypotension associated with impaired reflexes. The purpose of this study is to determine if the magnitude of the pressor response to atomoxetine at study entry, will be useful as a biomarker to differentiate those participants that will ultimately be shown to have pre-ganglionic (central) lesions (MSA) with those shown to have post ganglionic (peripheral) lesions (PAF and PD).

  Study phs001595

• Single-Cell and Spatial Multi-Omics Highlight Effects of Anti-Integrin Therapy Across Cellular Compartments in Ulcerative Colitis

  This is a focused, nested case-control study within our larger cohort "Immunoprofiling of the Blood and Intestine and Creation of a Gut Cell Atlas". This sub-study is titled as "Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis”. We examined the impact of Vedolizumab (VDZ), an anti-integrin antibody therapy, on the cellular landscape of ulcerative colitis (UC). While VDZ is primarily recognized for its role in preventing lymphocyte migration to the gut, the extent of its influence on other cellular populations has not been fully characterized. We used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to profile cells from both the blood and colon tissue samples. We pooled single-cell suspensions together before running scRNA-seq and CITE-seq, and subsequently deconvoluted the samples using the freemuxlet and demuxlet algorithms and variant call files (vcf) from bulk RNA-seq. This allowed us to assign cells to individual study subjects. We compared the cellular compositions of healthy individuals to those of UC patients undergoing treatment with VDZ or mesalamine (5-aminosalicylic acid/5-ASA). Our results revealed that VDZ induces significant changes in the variety and dynamics of mononuclear phagocytes within both the bloodstream and intestinal tissue, accompanied by subtle variations in lymphocyte populations. The dbGaP submission will provide raw sequencing data and participant phenotype data regarding disease and treatment status.

  Study phs003502

• Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function

  Endometriosis is a common gynecological disorder affecting 11% of reproductive aged women and is a leading cause of pain and infertility. We investigated global DNA methylation (DNAm) profiles in endometrium associated with endometriosis, menstruation, and genetic variation. Endometrial samples were collected from 984 patients with confirmed endometriosis (n=637) and women without endometriosis (n=347). Patients were recruited through the University of California San Francisco, USA, University of Melbourne, Australia, Endometriosis CaRe Centre in Oxford, UK, and EXPPECT Centre, The University of Edinburgh, UK, using the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (WERF EPHect) standardized protocols for tissue collection and processing, and participant characteristics and clinical annotation. DNA was extracted from samples and was use to generate DNAm data using the Illumina Infinium MethylationEPIC Beadchip and genotype data using the Axiom Precision Medicine Research array. Estimates from this study suggest that 15.4% of the variation in endometriosis is captured by DNAm. DNAm analysis identified significant differences in DNAm profiles and DNAm networks, associated with endometriosis, endometriosis sub-phenotypes, and menstrual cycle phases. Integration of DNAm and genetic data in a DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis highlighting target genes contributing to disease risk. This study identified novel factors affecting epigenetic regulation in endometrium associated with endometriosis risk and disease heterogeneity and provides an important data resource for reproductive medicine. Genotype data generated as part of this study are available on dbGaP and methylation data are available on GEO.

  Study phs003307

• Nasal MicroRNA during Bronchiolitis and Age 6y Asthma: MARC-35 Cohort

  We analyzed data from the 35th Multicenter Airway Research Collaboration (MARC-35) study to examine the relationship between nasal airway microRNAs (miRNAs) and the risk of developing childhood asthma. MARC-35 is a multicenter prospective cohort study which enrolled infants (age Structured interviews of the parents/guardians were performed by site investigators and clinical details were collected via emergency department and hospital inpatient chart reviews. Following the index hospitalization, trained study personnel conducted telephone interviews with parents/legal guardians at six-month intervals. Participants also underwent nasal swab sampling conducted by trained site personnel during the index bronchiolitis hospitalization and during an in-person follow-up examination at about age 6 years. Total RNA was extracted from nasal swab specimens using Trizol LS reagent (ThermoFisher Scientific, Waltham, MA) and the Direct-zol RNA Miniprep Kit (Zymo Research, Irvine, CA). Small RNA-seq was performed using the PerkinElmer NEXTFLEX® small RNA-seq v3 kit with Unique Dual Indexes (PerkinElmer, Waltham, MA) and sequenced on an Illumina NovaSeq6000 sequencer using an S2 50bp PE Flowcell (Illumina, San Diego, CA). Through dbGaP, limited de-identified phenotypic data (e.g., demographics) and RNA-seq FASTQ files will be made available. Among a cohort of infants hospitalized with bronchiolitis, we applied a small RNA sequencing approach and found miRNAs were associated with asthma risk factors, and highly expressed in lung tissue and immune cells (e.g., TH cells, neutrophils). They also played key roles in mechanisms relating to asthma, such as innate immunity, airway remodeling, and IgE regulation.

  Study phs003564

• NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)

  Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and the only leading cause of death that is steadily increasing in frequency. This project established a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,720 subjects were recruited, including control smokers and nonsmokers, definite COPD cases (GOLD Stage 2 to 4), and subjects not included in either group (GOLD 1 and PRISm). This cohort is being used for cross-sectional analysis, and long-term longitudinal follow-up visits after five years and after ten years are also being performed. The primary focus of the study is to identify the genetic risk factors that determine susceptibility for COPD and COPD-related phenotypes. Detailed phenotyping of both cases and controls, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome. The aims for this study are: Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, that will provide data to enable the broad COPD syndrome to be decomposed into clinically significant subtype; Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes; Distinct genetic determinants influence the development of emphysema and airway disease. The TOPMed analysis will include approximately 10,500 subjects with whole genome sequencing after quality control is completed. Comprehensive phenotypic data for COPDGene subjects is available through dbGaP study phs000179.

  Study phs000951

• Genetic Modifiers of Duchenne Muscular Dystrophy

  The primary determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether their dystrophin gene (DMD) mutation disrupts the mRNA reading frame or permits the expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, with candidate gene studies implicating several genes as potential DMD modifiers. This study undertakes a comprehensive genome-wide search for modifier loci influencing disease severity in DMD patients. The availability of subjects for such studies remains limited, resulting in modest sample sizes that challenge the GWAS design. To address this, we have implemented measures to minimize heterogeneity within the dataset at the dystrophin (DMD) gene itself, adopting a conservative approach to DMD mutation classification to limit the possibility of residual dystrophin expression. Additionally, the study employed statistical methods that are well-suited to smaller sample sizes, including the use of a novel linear regression-like residual for time to ambulatory loss and the application of evidential statistics, specifically the Posterior Probability of Linkage Disequilibrium (PPLD), to assess trait-SNP associations in the GWAS framework. With a sample size of 419 patients, this study has identified multiple candidate genetic modifier loci. The molecular data available in dbGaP includes 2,562,265 directly genotyped variants in 419 people using the Illumina Infinium Omni2.5Exome-8 Beadchip assay, achieving a genotyping rate of 0.998. The phenotypic data comprises age at ambulatory loss, steroid status, DMD gene mutation, and the PPLD value from the time-to-event (TE) phenotype.

  Study phs003680