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• A developmental cell atlas of the human thyroid gland

  Thyroid hormones are essential for health, but human thyroid development and cellular heterogeneity are poorly understood. We generated a high-resolution, spatiotemporal transcriptional atlas of human fetal thyroid, and examined its perturbations in trisomy 21 (T21), where aberrant thyroid development is associated with congenital hypothyroidism, and in papillary thyroid carcinoma (PTC). Normal tissue revealed two functional follicular cell states (fTFC1, fTFC2) with divergent PAX8 expression levels, persisting into adulthood. Additionally, the rare C-cell population was comprehensively profiled at single-cell resolution for the first time. T21 fetal thyroid was hypoplastic, with disrupted follicular morphology and altered expression of genes mediating cellular topology and extracellular matrix interactions. Finally, the transcriptional signals of both fetal follicular cell states were found to be perturbed in PTC. Overall, we defined a reference atlas for normal human fetal thyrocyte heterogeneity and provided novel insights into thyroid disorders.

  Dataset EGAD00001015783

• Anaplastic Oligodendroglioma AO Exome-seq data

  Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. 80% of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frame shift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumor type. Our analysis provides further insights into the unique and shared pathways driving AO.

  Dataset EGAD00001001452

• MOSAIC Window - Bladder dataset

  This dataset will include Spatial Transcriptomics, Single-Cell RNA-Seq, Bulk RNA-Seq, Clinical data, WES, and H&E data from 15 Muscle-invasive Bladder Cancer patients, treated with upfront cystectomy. Researchers from private or public institutions outside the MOSAIC Consortium will be able to apply to access this data and, pending approval, use the data for their research.

  Dataset EGAD50000000967

• MOSAIC Window Bladder Data

  This dataset will include Spatial Transcriptomics, Single-Cell RNA-Seq, Bulk RNA-Seq, Clinical data, WES, and H&E data from 15 Muscle-invasive Bladder Cancer patients, treated with upfront cystectomy. Researchers from private or public institutions outside the MOSAIC Consortium will be able to apply to access this data and, pending approval, use the data for their research.

  Dataset EGAD50000001251

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: KARE

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Korea Association Research Project (KARE) studies contributed 526 cases and 561 controls to T2D-GENES Project 1.

  Study phs001096

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Ashkenazi

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Ashkenazi study contributed 506 cases and 352 controls to T2D-GENES Project 1.

  Study phs001095

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Singapore

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Singapore studies contributed 1049 cases and 1177 controls to T2D-GENES Project 1.

  Study phs001097

• Type 2 Diabetes Genetic Exploration by Next-generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: London Life Sciences Population Study (LOLIPOP) UK South Asian

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The London Life Sciences Population Study (LOLIPOP) contributed 530 cases and 538 controls to T2D-GENES Project 1.

  Study phs001093

• PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study

  The PRE-DETERMINE Study is a prospective, multi-center study of 5,764 patients with a history of coronary artery disease (CAD) and documentation of either a prior myocardial infarction (MI) or mild to moderate left ventricular dysfunction (LVD) with left ventricular ejection fraction (LVEF) 35-50%. Patients were enrolled at 136 sites where information on baseline demographics, clinical characteristics, pertinent past medical history, lifestyle habits, cardiac test results, and medications were collected via electronic data capture. Electrocardiograms (ECG) along with a blood sample was also collected at baseline, sent to central laboratories, and stored for future analyses. Contrast-enhanced magnetic resonance imaging (CE-MRI) scans were collected on a subset of patients and analyzed. Enrollment closed in November 2013 and patients are now being followed centrally by the Clinical Coordinating Center via mail/phone to document interim non-fatal arrhythmic events and cause-specific mortality. Questionnaires that inquire about intervening implantable cardiac defibrillator (ICD) implantations, ICD therapies, cardiac arrest, and other pertinent cardiovascular endpoints are mailed to participants every six months, and follow-up telephone calls are made to non-responders. Study endpoints are being confirmed through review of medical records, interviews with next-of-kin, and autopsy reports, if available.The primary objective of PRE-DETERMINE is to determine whether biologic markers and ECGs can be utilized to advance sudden cardiac death (SCD) risk prediction in patients with coronary heart disease (CHD) and LVEF >30-35%. The overarching goal of the study is to identify a series of markers that alone or in combination specifically predict risk of arrhythmic death as compared to other causes of mortality among this at risk population of CHD patients with preserved LVEF> 30-35%. If biologic or ECG markers are identified that can specifically predict risk of ventricular arrhythmias, then these markers may serve as relatively inexpensive methods to identify those at risk. The public health impact of identifying markers could be quite substantial, leading to more efficient utilization of ICDs and advances in our understanding of mechanisms underlying SCD.Among the 95% of participants that provided a blood sample at baseline, genome wide genotyping using the Illumina Global Screening Array (GSA) has been performed. A total of 4,335 participants with European ancestry gave consent that allows genetic research and deposition of data into dbGaP.

  Study phs002940

• AVENIO Expanded ctDNA panel sequence alignments (BAMs)

  The AVENIO ctDNA Expanded Kit is a next-generation sequencing (NGS) liquid biopsy assay with a 77 gene panel (192 kb) containing genes in U.S. National Comprehensive Cancer Network (NCCN) Guidelines and emerging cancer biomarkers. This pan-cancer assay was applied to 100 plasma samples from patients with lung cancer undergoing treatment in the OSCILLATE trial. After 150 bp paired-end sequencing, reads were aligned to the human genome reference with the AVENIO Oncology Analysis Software. These files are the sorted non-deduplicated alignments generated by the analysis software used for subsequent variant, indel and CNV calling.

  Dataset EGAD50000000138

• Complex-I stratification of Parkinson's disease in the prefrontal cortex - bulk RNA seq

  Dataset corresponding to the bulk RNA seq dataset from prefrontal cortex for a total of N=98 samples. Tissue samples correspond to patients with idiopathic Parkison's disease (PD) with varying levels of Complex-I activity (N=79) and neurologically healthy controls (N=19). RNA seq was carried out using ribosomal depletion. A subset of these samples was additionally sequenced using single nucleus RNA seq and is available in the same Study as an additional Dataset.

  Dataset EGAD50000000433

• Admixture histories of São Tomé e Príncipe.

  Genotyping datasets used in the article "Nested admixture during and after the Trans-Atlantic Slave Trade in the island of Sao Tome" by Ciccarella M et al. 2025 The genotype data corresponds to 2,104,148 autosomal SNPs genotyped from the IlluminaOmni 2.5 Million BeadChip for 97 volunteer participants sampled on São Tomé e Príncipe, family unrelated at the 2nd degree based on population genetics analyses. In particular, the dataset is composed of 95 individual samples collected on São Tomé and 2 collected on Príncipe. SNP rsID, Chromosome position and genetic position in (bp) are in Build GRCh38.

  Dataset EGAD50000001348

• Single-cell RNA-Seq analysis of thymic ILC1 progenitors and NK cell differentiation This analysis involved a multiplexed sequencing run to study thymic innate lymphoid cells (ILCs) and NK progenitors. The generated data requires a demultiplexing file to separate and identify the individual sample tags for downstream analysis.

  This dataset contains multiplexed single-cell RNA sequencing (scRNA-seq) data from human thymic tissue, focusing on ILC1 progenitors and NK cell differentiation. The data were generated using the BD Rhapsody system and sequenced on the Illumina NovaSeq S4 platform. A demultiplexing file is required to assign sample identities.

  Dataset EGAD50000001157

• 10X single cell sequencing of HNT34 cocultured with Tcells with or without antibody targeting SLAMF6

  This dataset contains fastq-files from single cell 5' RNA sequencing of the AML cell line HNT34 and normal T cells following co-culture with and without an antibody blocking SLAMF6 (TNC-1). The libraries were prepared using 10X GEM-X Universal 5' Gene Expression v3 Reagent Kit. In total, the dataset contains sequenced gene expression libraries from four samples (HNT34 co-cultured with T cells from two different donors; for both donors there is one sample with and one sample without the blocking antibody).

  Dataset EGAD50000001573

• Variant calling for IMMU-SCCHN1 cohort

  The goal of IMMUcan is to understand how the immune system interacts with tumors and how therapeutic interventions influence this interaction. This cohort includes patients with confirmed locally recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who receive first-line treatment with immune checkpoint inhibitors (ICI) or ICI combined with chemotherapy. This dataset contains whole exome sequencing data from tumor and matching germline samples processed with the Vegan pipeline. It includes SNP and CNV calling.

  Dataset EGAD50000002205

• Neo-RT sWGS

  Paired plasma cell-free DNA (cfDNA) samples were collected from 11 breast cancer patients before and after radiotherapy. Sequencing libraries were prepared using the Agilent SureSelect XT HS2 kit and sequenced on the Illumina NovaSeq 6000 platform. Neo-RT (NCT03818100) is a non-randomised, single-arm feasibility study evaluating neoadjuvant radiotherapy combined with endocrine therapy in women with ER-positive, HER2-negative breast cancer. Eligible patients had grade 1 or 2 disease (grade 3 permitted if chemotherapy was contraindicated) and a palpable tumour size ≥20 mm, for whom radiotherapy was intended to facilitate breast-conserving surgery.

  Dataset EGAD50000002238

• Exome Sequencing to Identify Causes of Leukaemia Predisposing Congenital Neutropenias (2019-08-19)

  The objective of this study is to identify the causative genes in two unrelated congenital neutropenia families. We aim to whole exome sequence the affected individuals, unaffected siblings and parents in both cases in an effort to idenitfy the causative genetic mutation. Exome capture will be performed using Agilent SureSelect system. Subsequently, exome libraries will sequenced using the Illumina HiSeq platform. Sequence variant calling will be done in house and common variants excluded using public databases and data from unaffected family members. . This dataset contains all the data available for this study on 2019-08-19.

  Dataset EGAD00001005264

• Clinical and biomarker dataset

  Clinical & biomarker data from IMagyn050: treatment arm, treatment approach, outcome of surgery, ECOG PS, PD-L1 status, race, age, disease stage, progression free survival (investigator assessed), overall survival, histology, tumor mutation burden and status, genomic loss of heterozygosity, microsatellite status, BRCA1/2 mutation status, tissue of origin. Mutation status based on FoundationOne NGS for the following genes is also being provided: TP53, BRCA1, CCNE1, MYC, NF1, PIK3CA, RAD21, TERC, PRKCI, KRAS, RB1, BRCA2, ARID1A, AKT2, PTEN, KDM5A, NOTCH3, FGF12, ERBB2, CDK12, EMSY, WHSC1L1, BCL2L1, CDKN2A, GNAS, ARFRP1, ZNF217, SOX2, CCND2, FGF6, FGF23, LYN, MUTYH, AURKA, FGFR1, MCL1, MLL2, MYCL1, ZNF703, BRAF, MAP2K4, CREBBP, TSC2

  Dataset EGAD00001009797

• Congenital anosmia 1

  Congenital anosmias can be complete (the lack of a sense of smell) or specific (the inability to detect specific smells). To date, only a single recessive gene underlying complete anosmia has been identified. Here we sequenced the exomes of 10 individuals from a single family, including three with complete anosmia, across three generations to identify the genetic basis of congenital anosmia in this family. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001002210

• Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

  Genomic and transcriptomic data from a cohort of 35 RAS wild-type colorectal cancers. All 35 cases were DNA sequenced at baseline (BL) before treatment with single agent cetuximab. Progressive disease (PD)-biopsies were taken shortly after radiological progression and successfully exome sequenced from 24/35 cases. mRNA sequencing is available for 25 Baseline and 15 PD samples. ctDNA from 9 cases that progressed after prolonged cetuximab benefit were also deep sequenced.

  Dataset EGAD00001004501

• Transcriptomic Characterization of Human Innate T Cells

  We performed low input RNA-seq and single-cell RNA-seq on 7 lymphocyte populations with the objective of finding the common transcriptional programs shared among innate T cells. In brief, we drew blood from healthy donors and isolated CD4+ T cells, CD8+ T cells, Natural Killer cells, invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and two γδ T cell populations: Vδ1 and Vδ2. We performed low input RNA-seq on samples with 1000 cells each, for 6 healthy individuals, in duplicate. We performed single-cell RNA-seq with DNA-barcoded hashing antibodies to identify the cell type of origin for each cell. We found a common transcriptional program across lymphocytes that is gradually turned on as lymphocytes have a more "innateness" state, promoting effector functions and sacrificing proliferative capacity. Additionally, we performed low input RNA-seq for Vδ3-expressing γδ T cells and δ/αβ T cells for one healthy individual in duplicate (1000 cells per sample). This revealed δ/αβ T cells are transcriptionally more adaptive-like and Vδ3 more innate-like.

  Study phs002007

• 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

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA): GENOA is one of four research networks that form the NHLBI Family Blood Pressure Program (FBPP). From its inception in 1995, GENOA's long-term objective was to elucidate the genetics of hypertension and its arteriosclerotic target-organ damage, including both atherosclerotic (macrovascular) and arteriolosclerotic (microvascular) complications involving the heart, brain, kidneys, and peripheral arteries. Two GENOA cohorts were originally ascertained (1995-2000) through sibships in which at least 2 siblings had essential hypertension diagnosed prior to age 60 years. All siblings in the sibship were invited to participate, both normotensive and hypertensive. These include non-Hispanic White Americans from Rochester, MN (n =1583 at the 1st exam) and African Americans from Jackson, MS (N=1854 at the 1st exam). During the second exam (2000-2005), approximately 80% of participants were re-recruited. The GENOA data consists of biological samples (DNA, serum, urine) as well as demographic, anthropometric, environmental, clinical, biochemical, physiological, and genetic data for understanding the genetic predictors of diseases of the heart, brain, kidney, and peripheral arteries. Family Blood Pressure Program (FBPP): GENOA's parent program, the FBPP, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators began working together during the first funding cycle (1995-2000) and formalized this arrangement in the second cycle (2000-2005), creating a single confederation with program-wide and network-specific goals.

  Study phs000379

• ctDNA to predict risk of progression and death after trifluridin/tipiracil therapy

  Background. Late-line treatment in metastatic colorectal cancer (mCRC) can improve the prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. Despite many promising results, the role of circulating tumor DNA (ctDNA) analysis in trifluridin/tipiracil (FTD/TPI) treated mCRC patients is so far still elusive. Study design. This prospective non-interventional translational biomarker phase II study enrolled 30 metastatic CRC patients treated with FTD/TPI. The primary study aim was to identify a molecular biomarker to predict overall survival (OS) benefit upon FTD/TPI treatment. Methods. mCRC patients (60% male, 40% female) with FTD/TPI therapy were included. Molecular profiling in cell-free DNA from plasma was performed prior to treatment and on average 4, 8 and 12 weeks after FTD/TPI initiation. Tumor levels were assessed as the highest variant allele frequency (hVAF) and correlated with OS. Uni- and multivariate analyses for survival were performed with clinical variables. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG performance status. Results. Compared to previous data, our disease control rate of 30% was lower with a median OS of 8.1 months and a median PFS of 3.2 months. At baseline (BL) and the first two follow-ups (FU), a hVAF cut-off of 7.5% was most discriminative (BL HR 0.39 95% CI 0.16 - 0.98 P=0.0212, FU1 HR 0.30 95% CI 0.12 -0.77 P=0.0021, FU2 HR 0.23 95% CI 0.08-0.70 P=0.0004) whereas at the last follow-up the stratification was most pronounced at a 15% cut-off. An elevated hVAF trajectory over time was associated with a higher risk of death. Conclusion. ctDNA is detectable in a high proportion of mCRC patients. Changes in ctDNA levels are associated with survival among FTD/TPI therapy and may identify patients who benefit most from treatment in these late-stage disease.

  Study EGAS00001006883

• Transposable Elements in FTLD-TDP and ALS-TDP

  Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease involving the rapid and progressive loss of motor neurons. While a number of inherited mutations have been identified as causing ALS, the vast majority of cases are sporadic with no family history of disease. This has led to the model that ALS may be a complex syndrome with an unknown number of causal molecular pathways. However, nearly all ALS patient tissues display aggregates of the RNA binding protein TDP-43 (TARDBP/TAR DNA-binding protein), and mutations in the gene encoding this protein are known to cause ALS. We show that one of the normal functions of TDP-43 is to bind and regulate retrotransposons, repetitive sequences in the genome that are normally silent, due in part to the function of TDP-43. Furthermore, we demonstrate that many ALS patients with TDP-43 pathology also display de-silencing of retrotransposon RNAs, consistent with a loss of normal TDP-43 function. Those ALS patients that exhibit high levels of retrotransposon expression form a distinct subset of ALS subjects that also show other correlated alterations to the transcriptome. Using unsupervised machine learning algorithms, we identified three distinct molecular subtypes from the whole genomes and transcriptomes of a large cohort of 148 ALS patient samples. The retrotransposon re-activated subset formed 20% of ALS samples; two additional groups displayed signatures of oxidative stress (61%), and glial dysfunction (19%), respectively. Together these results demonstrate that retrotransposon re-activation is common in a subset of ALS patients with TDP-43 pathology.

  Study phs001889