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• Heart and Vascular Health Study (HVH)

  Objectives The Heart and Vascular Health Study (HVH) is a case-control study of risk factors for the development of myocardial infarction (MI), stroke, venous thrombosis (VT), and atrial fibrillation (AF). The study setting is Group Health, an integrated health care delivery system in Washington State. Background The HVH originated in 1988 with the examination of risk factors for MI. Over the ensuing years, the study has been funded by a series of grants, which have added case subjects with stroke, VT, and AF, and used a common control group. Study aims have focused on the associations of medication use with cardiovascular events. Starting in 1997, the study aims expanded to include genetic associations with cardiovascular disease. Participants recruited in 2009 or later and who provided blood samples for genetic analysis were asked for consent to deposit genetic and phenotype data in dbGaP. Design As part of the HVH study, case subjects were identified by searching for ICD-9 codes consistent with MI, stroke, VT, or AF, and medical records were reviewed to confirm the diagnosis. Control subjects were identified at random from the Group Health enrollment and were matched to MI cases. All subjects have an index date. For cases, the index date was assigned as the date that the cardiovascular event (MI, stroke, VT, or AF) came to clinical attention. For controls, the index date was a random date within the range of the case index dates. For both cases and controls, information was collected from the inpatient and outpatient medical record, by telephone interview with consenting survivors, and from the Group Health pharmacy and laboratory databases. Consenting participants provided a blood specimen. Genetic Research Genetic factors underlying cardiovascular disease are studied using DNA isolated from the blood samples.

  Study phs001013

• The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

  <p>We will apply whole genome sequencing of trio families to determine how patterns of germline mutation throughout the genome determine risk for Autism Spectrum Disorder (ASD). We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in trios and controls to determine the parent of origin of DNMs. Specific Aim 2 will identify hot spots for germline mutation based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of mutation hotspots with ASD in the discovery sample and in genomic datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

  Study phs001164

• AC-ICAM: An Atlas and Compass of Immune-CAncer-Microbiome Interactions in Colon Cancer

  Fresh frozen tumor samples and matched normal colon specimens from chemotherapy naïve, consecutive patients with a histological diagnosis of colon adenocarcinoma at Leiden University Medical Center (LUMC) were subjected to multi-omics profiling at Sidra Integrated Genomics Services, part of Sidra Medicine, Doha, Qatar. This resulted in a high-quality dataset of samples collected between 2001 and 2015. Multi-step QC was performed, including assessment of the quality of the nucleic acid extraction, sequencing, and genetic concordance between DNA/RNA sequences from the same patient. After QC, this resulted in RNA sequencing on 348 tumor samples, whole exome sequencing (WES) on 281 tumor-normal sample pairs (n=562 samples), TCR sequencing of the TCR β locus (TRB) for 114 tumor and 10 matched normal samples, and 16S rDNA sequencing on 246 tumor-normal sample pairs (n=492 samples) and 42 tumor only samples, and 167 WGS non human-aligned reads of the tumor samples. Extensive clinicopathological and survival data of the cohort are available. The median follow-up time for this cohort is 4.6 years, and the distribution of gender and pathological stage are within expected ranges for this patient population with a mean age of 68. We refer to this resource as the Sidra-LUMC (SILU) colon adenocarcinoma (COAD) Atlas and Compass of Immune-Colon cancer-Microbiome interactions (AC-ICAM)."Reprinted from Nature Medicine,Roelands, J., Kuppen, P.J.K., Ahmed, E.I. et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat Med (2023). https://doi.org/10.1038/s41591-023-02324-5, with permission from Nature."

  Study phs002978

• Columbia University Study of Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease

  Compared to Caucasians residing in the same community the incidence rate of Alzheimer's disease is approximately twice as high in Caribbean Hispanics. Moreover, Caribbean Hispanics represent a homogenous population with only a few founders. Replication of genetic associations in other ethnic groups provides supporting evidence that a putative gene is involved in the disease pathogenesis, and when different allelic variants within the same genes are associated with disease it can help to localize the pathogenic variant. SORL1 is an example of a candidate gene that was first identified in Hispanics and then confirmed in multiple ethnic and racial groups in a meta-analysis. For this project, we are genotyping 704 individuals in families multiply affected by Alzheimer's disease (166 families). These families were recruited in the United States, Puerto Rico and the Dominican Republic. In addition, we are genotyping 2491 individuals (960 patients with sporadic Alzheimer's disease and 1531 unrelated controls) phenotyped in a similar fashion totaling 3195 individuals. Both cohorts are followed at regular intervals of 18 to 24 months, and potential phenotypes available other than those related to Alzheimer's disease include body mass index, measured blood pressure, neurological history and examinations. More importantly, both studies are funded through 2014 and additional phenotypes could be added in successive waves. We propose a genome wide association (GWA) study of Alzheimer's disease and longitudinal changes in cognition and other age-related neurological and medical phenotypes. The goal will be to identify the chromosomal locations of genes underlying this disease and its related endophenotypes.

  Study phs000496

• Glial Cell Line-Derived Neurotrophic Factor (GDNF) Polymorphisms and Anxiety, Depression

  GDNF gene variants were studied as possible risk factors of depression or anxiety on a young sample. The association study involved eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF single nucleotide polymorphisms and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) on 708 Caucasian young adults with no psychiatric history. Results provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p=0.00070 and p=0.00138 for rs3812047 and rs3096140, respectively). Haplotype analysis confirmed the role of these SNPs (p=0.00029). A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. This is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140) and individual variability of anxiety using self-report data from a non-clinical sample. Reprinted from Kotyuk et. al., 2013 (Kotyuk, E., Keszler, G., Nemeth, N., Ronai, Z., Sasvari-Szekely, M., and Szekely, A. (2013). Glial Cell Line-Derived Neurotrophic Factor (GDNF) as a Novel Candidate Gene of Anxiety. PLoS One,8, (12) PMID: 24324616), with permission from Publisher (All content of articles published in PLOS journals is open access. You can read about our open access license here: http://www.plos.org/about/open-access/. To summarize, this license allows you to download, reuse, reprint, modify, distribute, and/or copy articles or images in PLOS journals, so long as the original creators are credited (e.g., including the article's citation and/or the image credit); Laura Perry; Staff EO;PLOS ONE)

  Study phs000713

• Microvascular Permeability, Inflammation, and Lesion Physiology in Endometriosis: A Microphysiological Systems Approach

  The goal of the study is to identify novel molecular pathways involved in the etiology of endometriosis and to develop in vitro model systems to enable the study of the mechanisms regulating reproductive function. Using a physiomimetic modeling approach, primary tissue samples of the human endometrium derived from patients diagnosed with and without endometriosis and/or endometriotic diseases (e.g. adenomyosis) were used for secondary analysis using multi-omic systems biology analysis and to build tissue engineered models. We performed single cell RNA sequencing (scRNA-Seq, N=6)) to study the cellular and transcriptomic composition of the endometrial tissue microenvironment and proteomics (LC-MS/MS) to study protein-level signaling pathways and the matrisome of the native endometrium. Systems biology analysis of these datasets helped identified a putative dysregulated inflammatory signaling pathway in endometriosis patients compared to controls. Moreover, subsets from these scRNA-Seq and proteomic datasets were used to aid the design of a synthetic extracellular matrix hydrogel as an in vitro platform for the culture of endometrial cells. Tissue-engineered synthetic PEG hydrogel enables the simultaneous co-culture of endometrial epithelial organoids and stromal fibroblasts in a fully defined, 3D, and tunable environment. We demonstrated that the in vitro co-culture model recapitulates key phenotypic processes observed across the human menstrual cycle in response to sex hormone stimulation through both biochemical and transcriptomic (bulk RNA-sequencing) analysis. This model will enable future mechanistic studies that examine origins of endometriotic disease phenotypes. The transcriptomic data generated for this study including the scRNA-Seq data from primary human endometrial tissues and the bulk RNA-Seq datasets from the experimental co-culture models is available through dbGAP.

  Study phs003326

• Single-cell Transcriptome Profiling of Treatment-naïve and Post-treatment Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

  Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Investigation of cancer cells and tumor microenvironment (TME) following chemotherapy is critical for unraveling the mechanisms of resistance. In this study, we analyzed scRNA-Seq data from 56 CRCs including treatment-naïve tumors (25 microsatellite stable (MSS) tumors and 7 tumors with microsatellite instability (MSI)); and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). We observed in treatment-naïve MSS CRC that right-sided tumors are more immunogenic with higher numbers of B cells and CD8+ T memory effector cells than left-sided tumors. MSI CRC were even more immunogenic then MSS CRC and were characterized by elevated Tregs in their TME. In the post-treatment CRC there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. We also observed two fibroblast subtypes in CRC, one of which was enriched in progressors and was associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated exhausted CD8+ T memory cells and monocytes suggesting a pro-inflammatory TME. In tumor cells in progressor group we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related marker CD24. In summary, scRNA-Seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features of CRC based on location, metastasis status, MSI status and treatment response status.

  Study EGAS50000000830

• Exploration of coding and non-coding variants in cancer using GenomePaint.

  GenomePaint (https://proteinpaint.stjude.org/genomepaint) is a dynamic visualization platform for whole-genome, whole-exome, transcriptome, and epigenomic data, featuring a novel design that captures the inter-relatedness between DNA variations and RNA expression. Regulatory non-coding variants can be inspected and discovered along with coding variants, and their functional impact further explored by examining 3D genome and/or ChIP-seq data generated from cancer cell lines. Further, GenomePaint correlates mutation and expression patterns with patient outcomes, and can display external data such as adult cancer datasets and user-provided custom tracks. We used GenomePaint to analyze multi-omics data from 3,652 pediatric cancers representing 16 histotypes, and demonstrate the visualization features through examples, including two that led to new insights into oncogenic mechanisms in pediatric cancer. The first is the discovery of a new class of pathogenic recurrent variants that cause aberrant splicing, disrupting the RING domain of CREBBP, a driver gene frequently mutated in relapsed pediatric leukemia. The second is the cis-activation of the MYC oncogene in a subset of B-lineage acute lymphoblastic leukemia (B-ALL) via duplication of the NOTCH1-MYC enhancer (N-ME), previously discovered only in T-lineage ALL. The regulatory impact of N-ME enhancer amplification was initially confirmed by allelic imbalance in published gene expression and ChIP-seq data and verified by additional Capture-C and fluorescence in situ hybridization data generated by follow-up experiments. These examples demonstrate the power of GenomePaint in enabling not only data visualization but also integrative genomic analysis that can lead to novel biological insight for follow-up experimental validation.

  Study EGAS00001004669

• Mutational patterns and regulatory networks in epigenetic subgroups of meningioma (H033)

  DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign-1, 2, 3, intermediate-A, B and malignant. Here, we set out to identify subgroup-specific mutational patterns and pathway regulation. Whole-genome-sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic and 22 radiation-induced (Mrad) meningiomas. RNA sequencing was added for 18 cases and chromatin-immunoprecipitation for the enhancer mark H3K27ac followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural alterations were found to contribute to the spectrum of mechanisms inactivating NF2 in sporadic meningioma similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3 was detected in both sporadic meningioma and Mrad, but distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. In general, the malignant MC presented a significantly higher exposure to AC3 and higher genomic instability beyond the mutational load than the other MCs. Pathway analysis of the ChIP-seq clusters revealed that the FOXM1 is most differentially activated in high-grade cases, along with super enhancer recruitment near HOX genes and respective upregulation of expression. This data further elucidate the biological mechanisms differentiating meningiomas of different WHO grade and epigenetic subgroups and suggest leveraging the genomic instability as novel therapeutic targets.

  Study EGAS00001003481

• cfDNA dataset from the urine supernatant of ovarian cancer patients and healthy controls

  Background Ovarian cancer is the deadliest gynecological malignancy worldwide, due to frequent diagnosis at advanced stage. Simple and non-invasive methods for earlier and accurate detection are urgently needed. Here, the presence of tumor-derived DNA in home-collected urine, cervicovaginal self-samples and clinician-taken cervical scrapes of ovarian cancer patients was explored by DNA methylation and copy number analysis. Methods A total of 428 samples (urine, cervicovaginal self-samples, and clinician-taken cervical scrapes) of 110 healthy controls and 54 patients with benign (n=25) or malignant (n=29) ovarian masses were analyzed. Different urine fractions were examined (full void urine, urine supernatant, and urine sediment). All samples were tested for 12 methylation markers by quantitative methylation-specific PCR. Shallow whole-genome sequencing was performed to detect copy number aberrations and verify the presence of tumor-derived DNA. Results Full void urine was most discriminatory between healthy controls and ovarian cancer patients (C2CD4D, p=0.008; CDO1, p=0.022; MAL, p=0.008), followed by cervical scrapes (C2CD4D, p=0.001; CDO1, p=0.004). A significant difference between benign and malignant ovarian masses was only observed for GHSR in the urine sediment (p=0.024). Methylation levels in cervicovaginal self-samples did not discriminate between healthy controls, benign and malignant ovarian masses. Copy number changes were identified in 17% of urine supernatant samples and smaller fragment sizes were seen in urine supernatant samples with a high tumor fraction. Conclusions This study demonstrates the presence of ovarian cancer-derived DNA in home-collected urine. Additional studies are warranted to further explore the clinical applicability of this approach.

  Study EGAS00001007238