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• Patient-derived organoids as predictive models for drug testing and repurposing in glioblastoma therapy

  Glioblastoma multiforme (GBM) remains a highly aggressive brain tumor with limited treatment options and poor prognosis. Temozolomide (TMZ) is the only approved first-line therapy, but frequent resistance limits its efficacy, highlighting the urgent need for alternative treatments. Patient-derived glioblastoma organoids (GBOs) offer a promising preclinical model for personalized drug testing and therapy development.

  Study EGAS50000001221

• Shedding light over COVID-19 susceptibility and severity

  “One of the most remarkable features of SARS-CoV-2 infection is the variation in consequence ranging from asymptomatic to life-threatening” state the authors of the majestic Nature paper released in accelerated pre-view on July 2021. This variation in consequences represent not only an issue of burning medical relevance, but also a scientific and intellectual challenge for scientists around the globe. Researchers are known to be easily triggered by a challenge, and they recently demonstrated to be even better at double their efforts to focus on an urgent societal need. In this work led and coordinated by the COVID-19 Host Genetics Initiative (COVID-19 HGI), researchers gathered data from 49,562 cases and two million controls from 46 studies performed worldwide. The majority of the data has been deposited at the EGA, where 29 datasets have been collected under the study number EGAS00001005304. Data gathered from diverse sources conferred a huge robustness to the results. Genetic data from different ancestry origin were included in the analyses, even though data from patients with European origin was highly predominant (approx. 75%). Separated analysis of the different ancestries gave rise to relevant differences in the results, highlighting how important it is to take this aspect in consideration for future studies. Data from the individual studies was compiled into three categories according to COVID-19 severity for a meta-analysis: (a) critically ill cases (b) moderate or severe cases (c) all cases. They were paired with non-COVID-19-reported controls. All three analysis resulted in a total of 13 genetic loci associated with COVID-19 severity. Out of those, 9 loci associated specifically with critical illness, while 6 (a few overlapped) associated with moderated illness. Some genomic position matched previous findings. Interestingly, working with such an enormous amount of data allowed the depth to discriminate association with disease susceptibility vs severity, an issue of large medical relevance. Several loci mapped into biological relevant genes, like TYK2, PPP1R15A and FOXP4, previously implicated in immune response and/or lung functions. Researchers participating in the COVID-19 Host Genetics Initiative have worked in an unprecedented time-tight collaboration, prioritizing data sharing and collective results to tackle the pandemic affecting the world. The scientific community won’t miss any of the lessons to learn from this, and the EGA is ready to keep working to enable safe data sharing and fruitful collaborations.

  Blog covid-19-susceptibility-and-severity

• A Study of the Genetic Causes of Complex Pediatric Disorders

  The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. CAG has committed to releasing genotype and phenotype data for 4000 individuals diagnosed with asthma, ADHD, atopic dermatitis, GERD (1000 for each), and 1000 individuals on the upper and lower ranges of Low-Density Lipoprotein (LDL) levels to dbGaP. We will also release genotype/phenotype of 3000 controls. Relevant phenotype data includes primary diagnoses (ICD9 codes), secondary diagnoses (ICD9 codes), medical procedures/tests conducted in relation to the phenotype, and a listing of relevant medications. Further details of CAG's research programs and capacity are available at: http://www.caglab.org

  Study phs000490

• Urethral Microbiome of Adolescent Males

  Urethral microbiome of adolescent males is designed to characterize the microbial communities resident in the urethra of young men, to identify differences in these communities as a function of race/ethnicity, circumcision status, sexual exposures, and uro-genital symptoms. We collect detailed sexual behavior and symptoms data using cellular telephones with Internet access. Specimens are routinely collected at monthly intervals, and intermittently following reported symptoms, specific sexual exposures, or identification of a sexually transmitted infection. We also collect periodic samples from the penile coronal sulcus to better characterize its relationship to the urethral micriobial communities. Participants are ages 14 - 17 at enrollment, and prior history of sexual exposure is not required for participation. Parental permission is obtained for each participant. The planned duration of followup is up to 4 years allowing for prospective observation of both physical and behavioral maturation from middle adolescence into young adulthood. The overall objectives of the project are to better characterize the healthy male urethral microbiome, and to use this information to better understand acquisition of urethritis and sexually transmitted infections, as well as chronic genital pain and prostatitis syndromes that become common among young adults.

  Study phs000259

• Genome-Wide Discovery of Novel Breast Cancer Predisposing Mutations

  Cancer risk shows clear heritability, but the inherited genetic factors remain largely unknown. This project will seek to identify new genes in which mutations confer hereditary risk for early onset breast cancer, with important implications for both biological understanding and clinical prediction and prevention. Identifying cancer predisposing mutations can provide new biological insights and significantly impact important clinical decision making regarding treatment, surveillance and preventive approaches. Examples include the BRCA1 breast cancer susceptibility gene, which affects treatment decisions (surgical management), surveillance (frequent breast MRI) and prevention (oophorectory for prevention of ovarian cancer). Hereditary early onset breast cancer patients commonly present to Cancer Genetics clinics, but the majority of these patients do not have identifiable mutations in known candidate genes. Here, we will perform whole exome sequencing to discover novel cancer susceptibility genes. The patients have been recruited from Memorial Sloan Kettering Cancer Center (PIs Kenneth Offit and Zsofia Stadler) and Massachusetts General Hospital (PI Daniel Haber). All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000822

• eMERGE Phase III Clinical Center at Partners HealthCare

  The Partners HealthCare Biobank is a large research data and sample repository working within the framework of Partners Personalized Medicine. It provides researchers access to high quality, consented samples to help foster research, advance understanding of the causes of common diseases, and advance the practice of medicine. The Partners Biobank provides banked samples (plasma, serum and DNA) collected from consented patients. These samples are available for distribution to Partners HealthCare investigators with appropriate approval from the Partners Institutional Review board (IRB). They are linked to clinical data that originates in the Electronic Medical Record (EMR), as well as additional health information collected in a self-reported survey. The Partners Biobank will be genotyping 25,000 subjects with the Illumina Multiethnic Beadchip 1.6 million SNPs with exome and custom content (> 60,000 LoFs). Of the participants genotyped so far, 4929 of 4962 (99.3%) individuals have genotype data that passed the default quality thresholds for the Infinium array (call rate >= 0.99). We are submitting the genotype data to dbGaP for 4929 subjects with 12 phenotypes (based on icd9 codes). We will do annual releases until we reach the full 25,000 genotyped subjects.

  Study phs000944

• Epigenetic Biomarkers of Aging

  The aim of the study was to discover new epigenetic biomarkers of aging. We used a genome-wide screen for genetic loci showing consistent changes of DNA methylation with progressive aging. Blood DNA samples from 19 apparently healthy individuals aged 22-80 years obtained from the NINDS repositories were analyzed for DNA methylation using Reduced Representation Bisulfite Sequencing. We followed the New England Biolabs (NEB) protocol for methylated adaptors as described previously. Briefly, 1 microgram of genomic DNA was spiked with 100 picograms of lambda phage DNA as the unmethylated standard and digested with MspI endonuclease at C’CGG sites. Ends of restriction fragments were filled in, 3’-dA tailed and methylated adaptors were ligated to the ends of restriction fragments. Bisulfite treatment using the Epitect kit (Qiagen) followed. Bisulfite-converted libraries were amplified using EpiMark Taq DNA polymerase (NEB) and primers with dual barcode indices. The libraries were pooled and sequenced on Illumina HiSeqX instrument using paired end reads of 150 bases. We used Bismark v0.23.1 to align the sequences to hg19 human genome assembly. We used methylKit v1.22.0 to analyze differential methylation in individuals of different ages.

  Study phs003046

• Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. This record includes plasma metabolomics and plasma proteomics data. Genotype data for 3527 CRIC Study partcipants is available at dbGaP in phs000524, "Chronic Renal Insufficiency Cohort (CRIC)-GWAS". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP.More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at the BIBLIOGRAPHY for the Chronic Renal Insufficiency Cohort (CRIC) Study.

  Study phs003709

• Global Anaplastic Thyroid Cancer Initiative

  Thyroid cancer is the most common endocrine malignancy. Most thyroid cancers are of the well-differentiated (non-aggressive) phenotype, and are almost always cured with standard treatments. In contrast, anaplastic thyroid cancer (ATC) is rare, accounting for only 1% of thyroid cancers, however it is perhaps the most lethal human malignancy with an average survival of 3 to 6 months. ATC presents with dramatic and rapid onset of airway and esophageal blockage with frequent spread to the lungs. Interestingly, 21–79% of ATCs have coexisting areas or a previous history of well-differentiated cancers. Although this suggests a progression from well-differentiated cancers to ATC, to date there is little molecular conformation that such a progression exists versus de novo generation of ATC. As ATC is extremely rare and most cases are inoperable, there are a paucity of tissue samples for study at any one center. The Global Anaplastic Thyroid Cancer Initiative (GATCI) aims to unite international institutions in order to pool samples (ATC with or without a paired well-differentiated component) for a comprehensive analysis of the genomic landscape of this disease.

  Study EGAS00001002234

• Determination_of_cell_specific_regulatory_enhancers_in_hematopoetic_models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise “experimental noise” and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

  Study EGAS00001000586