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• Admixture Mapping of Staphylococcus aureus Bacteremia

  In this study, we used admixture mapping to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to Staphylococcus aureus bacteremia (SAB) in a sample of African Americans. A total of 565 adult African Americans were genotyped for admixture mapping. Cases were unique African American adult inpatients with monomicrobial SAB (N=390) and controls are age-matched adult African American inpatients with no current or past S. aureus infection (N=175). After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P = 4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB.

  Study phs001441

• Investigation of respiratory chain integrity in skeletal muscle in Parkinson's disease

  The aim of this study is to investigate mitochondrial dysfunction in skeletal muscle as a potential biomarker for identifying a distinct subtype of Parkinson’s disease (PD) characterized by mitochondrial complex I (CI) deficiency (CI-PD). Based on previous post-mortem findings, the study hypothesizes that widespread CI deficiency is present in a subset of PD patients and could be detectable in clinically accessible muscle samples. By analyzing mitochondrial function in muscle biopsies from individuals with PD and healthy controls, the study seeks to explore the extent of mitochondrial dysfunction in PD and identify a stratification marker for future diagnostic and therapeutic interventions. This study is part of the STRAT-PARK initiative, a longitudinal cohort study that aims to stratify neurodegenerative parkinsonisms into biological subtypes using a biomarker-based approach (https://doi.org/10.1016/j.pneurobio.2024.102603).

  Study EGAS50000000671

• Effects of busulfan, fludarabine and clofarabine treatment on human small intestinal organoids generated from healthy donors

  The intestine is vulnerable to chemotherapy-induced toxicity due to its high epithelial proliferative rate, making gut toxicity an off-target effect in several cancer treatments, including conditioning regimens for allogeneic hematopoietic cell transplantation (HSCT). In HSCT, intestinal damage is an important factor in the development of Graft-versus-Host Disease (GVHD), an immune complication in which donor immune cells attack the recipient's tissues. Here, we developed a novel human intestinal organoid-based 3D model system to study the effects of chemotherapy-induced intestinal epithelial damage at the RNA level. We show that chemotherapy conditioning specifically reprograms the intestinal epithelial transcriptome after treatment with either busulfan (3.5μM), fludarabine (15μM) or clofarabine (0.5μM) for 24h. This knowledge can potentially enable us to understand which changes undergo in healthy tissues upon conditioning and how those are related with immune activation typical in GVHD.

  Study EGAS00001007550

• Investigation_of_mutational_signatures_associated_with_DNMT3A_deficiency_

  Mutational signatures have been shown to be attributable to specific genetic contexts, such as mutations in DNA repair genes. DNMT3A is a DNA methyltransferase that helps maintain the DNA methylation pattern in a site-specific manner and may participate in DNA repair or the stress response. We have identified an adult individual who is a germline mosaic for a DNMT3A mutation. We have obtained clonal lymphoblastoid cells (LCLs) from the subject representing both WT and mutant lines grown in the same individual for >50 years. These clones represent a unique opportunity to examine the mutational impact of the DNMT3A mutation in a well-controlled setting. Our goal is to perform WGS on whole blood, representing the pool, as well as several WT and several mutant clones, in order to investigate the contribution of DNMT3A to mutation rates and signatures.

  Study EGAS00001002329

• Detection and Targeting of Splicing Deregulation in Pediatric Acute Myeloid Leukemia Stem Cells

  This study evaluates the gene expression and splicing changes between pediatric patients with and without Acute Myeloid Leukemia (AML) and pediatric and adult patients with AML. We obtained bone marrow or peripheral blood from patients and isolated CD34+ stem and/or progenitor cells from pediatric patients with AML (10) or without AML (6) and adult patients with AML (5). In parallel, a targeted analysis for known, deleterious, genetic mutations in the KRAS, NRAS, and KMT2C genes identified 2, 5, and 6 AML patients with alterations, respectively. Additionally, Tapestri analysis further identified a mutation in the intronic region of the SF3B1 gene in multiple pediatric AML patients. RNA-Seq was performed on the purified cell populations at The Scripps Research Institute Next Generation Core on an Illumina NextSeq 500 sequencer with 150bp paired-end reads.These datasets revealed that, similar to adult AML, pediatric AML samples were enriched for Leukemia Stem Cells (LSC) markers. A deeper analysis showed widespread dysregulation of splicing in pediatric AML samples compared to age-matched non-leukemic samples. In addition, the splicing regulator RBFOX2 was downregulated with an accompanying increase in specific CD47 splice isoforms in the pediatric AML samples. Thus, the increased presence of LSCs in pediatric AML is possibly driven by global splicing deregulation, and the treatment with splicing modulators like Rebecsinib has a potential therapeutic value for eradicating LSCs in these patients.

  Study phs003196

• Sequencing data of the ampulla and fimbriae of the fallopian tube in pre-menopausal women

  A total of 10 pre-menopausal patients were recruited for this study. Sequencing of both the fimbriae and ampullary region of the fallopian tubes was performed using 10x Genomics single-cell RNA-seq and ATAC-seq. For one patient, data were sequenced across 4 lanes, while the remaining patients' data were sequenced in 2 lanes each, resulting in a total of 44 sequencing datasets for each platform.

  Dataset EGAD50000000889

• Impact of Race and Genetic Factors on Beta Blocker Effectiveness in Heart Failure

  Heart Failure (HF) continues to be an enormous public health problem, despite the many advances in its pharmacotherapy over the past 25 years. The availability of multiple therapeutic options for HF requires individualization of therapy. However, there are currently insufficient tools to guide the optimal selection of therapy. The expansion of human genomic information has led to exciting new opportunities to improve the selection of drug therapy. In order to evaluate whether genetic variation impacts outcomes and drug response in heart failure, we performed a cohort study of patients with heart failure. Our overall plan was to recruit patients who have heart failure and receive treatment through HAP-HFMG. This allowed us to collect clinical outcomes, and quantify medication adherence via electronic pharmacy claims data. We collected whole blood samples for genetic analysis. We then tested whether genetic variants can predict patient outcomes (survival) in the context of their medical therapy (drug exposure). The primary medications of interest were beta blockers. Outcomes were modeled overall, accounting for the amount of exposure to the agent, and adjusting for baseline characteristics.

  Study phs001501

• Efficacy of Bitter Taste Blockers on Flavor Acceptance in a Human Population

  The goal of this project is to determine variation in human bitter perception and the effectiveness of bitter blockers in individuals of different genotypes. The project is based on the parent project titled "Efficacy of bitter taste blockers on flavor acceptance in pediatric population", which addresses how bitter taste perception affects medication compliance. As a part of the parent project, mothers and their children were recruited from the general population of metropolitan Philadelphia through print and internet media as well as from a database of past research participants. Adults (mothers) were evaluated in the laboratory for bitter taste perception for a variety of "Generally Recognized As Safe" (GRAS) bitter compounds using the general Labeled Magnitude Scale (gLMS) which allows subjects to rate sensory intensity. Mothers were also evaluated for perception of the liquid formulation of the drug KaletraTM, a recommended 1st line treatment for infants with HIV infection, whose taste is rejected by some children and accepted well by others. DNA samples from mothers were genotyped as a part of this study to identify (1) novel genes associated with human bitter perception and (2) the ability of compounds to block bitterness.

  Study phs000839

• Changes in alternative splicing and associated neo-antigens due to therapy

  Recent studies have identified alternative splicing (AS) as a novel source of neoantigens for immunotherapy. Surprisingly little is known about the AS milieu in recurrent glioblastoma (GBM), despite this being the venue for most clinical trials. We profiled 29 primary-recurrent paired human GBM specimens via RNA sequencing and re-analyzed RNA-sequencing data from non-malignant human brain tissues. From these data, we reconstructed the landscape of AS in GBM through recurrence and contrasted that to isoforms observed in non-malignant brain. The AS events we identified were cross-referenced with single-cell GBM atlases to determine cell-type specific splicing patterns. From this we identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies. We found recurrent-specific isoforms of mitogen-activated kinase pathway genes which are expressed exclusively by GBM stem-like cells that enhance invasiveness. These studies shed light on the effect of therapy on AS and identify novel targets for emerging immunotherapies.

  Study EGAS00001004524

• Molecular defects in pseudohypoparathyroidism or related disorders

  Maintaining calcium levels within a narrow normal range is of critical importance for numerous different cellular functions. One of the most important regulators of blood calcium levels is parathyroid hormone (PTH), which mediates its actions through the PTH/PTHrP receptor, a Gαs-coupled receptor. Few inherited disorders are characterized by diminished blood calcium levels and elevated blood phosphate levels; some of these disorders are caused by too little PTH synthesis and/or secretion (hypoparathyroidism, HP), while others are caused by resistance towards PTH (pseudohypoparathyroidism, PHP). Only few of the inherited forms of HP (<10%) have been defined at the molecular level. In contrast, genetic mutations have been identified for several inherited forms of PHP. For example, PHP type Ia (PHP-Ia) is caused by maternally inherited mutations in those GNAS exons that encode Gαs, while autosomal dominant PHP type Ib (AD-PHP-Ib) is caused by maternal inherited deletions within or up-stream of GNAS, which are associated with abnormal GNAS methylation. However, a large number of patients with PTH-resistance and thus hypocalcemia show GNAS methylation changes, but their underlying genetic defects have not yet been defined at the DNA level. These "sporadic" patients may be affected by an autosomal recessive form of PHP-Ib (AR-PHP-Ib), which is most likely not linked to the GNAS locus. In our studies, we propose to search through exome sequence analyses for novel genetic mutations responsible for novel autosomal dominant forms of HP that are not caused by mutations in the known disease-causing genes; some of these families are large enough to perform genetic linkage studies. We furthermore propose to search for the genetic mutation(s) responsible for the autosomal recessive variant of PHP-Ib through the analysis of whole exome sequences; for these studies we focus particularly on patients, whose parents are likely to be consanguineous. The proposed efforts are expected to lead to the identification of novel genes that are involved in parathyroid development and function (HP) and genes that are involved in the establishment or maintenance of GNAS methylation (AR-PHP-Ib).

  Study phs000476