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• PROGRESS/ELEMENT DNA Methylation Study

  An extension to the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort of Mexico City, the Programming Research in Obesity, GRowth, Environment and Social Stress (PROGRESS) Cohort is an ongoing longitudinal pre-birth cohort, established in 2006 in Mexico City, partnering Icahn School of Medicine at Mount Sinai with Harvard University and the National Institute of Public Health in Mexico, which was designed to study the effects of prenatal exposure to toxic metals, air pollution, phthalates, and stress on childhood development. Pregnant women of 18 years of age and older, pregnant for less than 20 weeks of gestation, had no documentation of heart or kidney disease, no use of steroids or anti-epilepsy drugs, no daily alcohol consumption, had telephone access, and planned to live in Mexico city for the following 3 years, and receiving care through the Mexican Social Security System were initially enrolled (n=1,054). In addition to clinical, demographic and exposure data collected, cord blood was collected to interrogate DNA methylation across the genome for over 300 mother-child dyads. Clinical assessments and exposures were captured during several life stages, including prenatal, infant (0-1 year), youth (1-18 years), and adulthood (mother). The PROGRESS cohort added well-documented phenotyping of children for obesity, metabolic dysfunction, respiratory outcomes, and cardiovascular outcomes, as well as measures of air pollutant, personal care/consumer product, non-chemical stress, and metal mixture exposures. No clinical trials were conducted in this cohort. The data collected in this study should provide a unique resource to investigate DNA methylation as it relates to several environmental exposures and adverse cardiometabolic and neurocognitive health in mothers and children from a prospective birthing cohort. For access to demographic, clinical, and exposure data please directly contact study principal investigators.

  Study phs002754

• Transcriptomic and Clonal Characterization of T Cells in the Human Central Nervous System

  The cerebrospinal fluid (CSF) is thought to be a main route for immune surveillance in the central nervous system (CNS). Understanding the composition and state of CSF in healthy individuals may provide insight into perturbations present during neuroinflammation. Here, we have used single-cell RNA and TCR sequencing to profile CSF and peripheral blood mononuclear cells (PBMCs) from healthy individuals and patients with relapsing-remitting multiple sclerosis (MS), a chronic autoimmmune disease. In addition, with the goal of understanding how transcriptional artefacts are introduced in transcriptomics experiments, we have performed single-cell and TCR sequencing to profile PBMCs from a healthy individual that were processed with the same enzymatic digestion used for tissues (such as the brain) in the presence or absence of transcription inhibitors. 

  Study phs002222

• RNA sequencing data from glioblastoma primary cell lines treated with indisulam

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The splicing-modulating drug indisulam was investigated for its potential to induce aberrant transcriptomes, potentially increasing ncTSAs, subsequently predicted by NovumRNA. Four glioblastoma primary cell lines were derived from patient Cavitron Ultrasonic Aspirator (CUSA) material, cultured as neurospheres, and treated with indisulam or vehicle control. RNA was extracted at 6 and 16 hours post-treatment and sequenced using the NovaSeq platform. The resulting RNA-seq data was analyzed with NovumRNA, using healthy brain GTEx samples as controls, to identify and validate ncTSAs induced by indisulam treatment. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000680

• UCSF Pediatric Bithalamic Glioma Genome Project

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 pediatric bithalamic diffuse gliomas, a lethal brain tumor of childhood for which the genetic basis is largely unknown. We identified that bithalamic diffuse gliomas harbor frequent mutations in the EGFR oncogene in the absence of accompanying gene amplification and only rare histone H3 mutation. These EGFR mutations were either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain). Accompanying alterations included frequent TP53 mutation, CDK6 amplification or CDKN2C mutation, and BCOR and BCORL1 mutation or deletion.

  Study EGAS00001004033

• Most HCCs in Taiwan show the mutational signature of aristolochic acid

  Plants in the genus Aristolochia contain the mutagen aristolochic acid (AA) and have been widely used in traditional medicines and for weight loss. AA binds covalently to genomic DNA and induces a highly distinctive mutational signature. While AA involvement in urinary-tract cancers in Taiwan is known, the possible role of AA in hepatocellular carcinomas (HCCs) in Taiwan has not been examined. Here, we whole-exome sequenced 98 unselected HCCs from Taiwan and analyzed the mutational signatures for evidence of AA mutagenesis. Remarkably, more than 78% of HCCs showed strong evidence of AA mutagenesis, often associated with high mutation burdens. Non-synonymous mutations in genes known to be HCC driver genes were detected. Importantly, we elucidated the potential of immunotherapy in this cohort of liver cancer patients.

  Study EGAS00001002301

• Heterogeneity in Lysosomal Storage Disorders

  Gaucher disease (GD) is an inherited lysosomal storage disorder caused by biallelic pathogenic variants in GBA1, which encodes glucocerebrosidase. Additionally, GBA1 variants are a well-established genetic risk factor for Parkinson's disease (PD), leading some PD research centers to incorporate GBA1 screening to identify patients who may benefit from targeted therapeutics. However, detecting GBA1 variants remains challenging due to the gene's high sequence homology with its pseudogene, which can give rise to complex recombinant alleles. This study evaluates the performance of Gauchian, a recently developed software tool for identifying GBA1 variants from whole genome sequencing (WGS) data. The assessment was conducted in a cohort of 90 individuals with GD and five GBA1 heterozygotes, all previously characterized through Sanger sequencing. While Gauchian successfully identified the most common genotypes, it demonstrated limitations in detecting rare or de novo variants due to its restricted internal database and heavy reliance on intergenic structural variants. These limitations led to misclassified homozygosity, incomplete genotyping, and undetected recombination events, ultimately reducing the tool's utility for comprehensive variant screening and precluding its application in diagnostic settings. The study dataset includes WGS from the 90 individuals used in the Gauchian pipeline. This data will be available through dbGaP to facilitate further research on GBA1 variant detection, genotype-phenotype correlations in GD and PD, and the development of improved bioinformatics tools for complex variant identification.

  Study phs003459

• Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping

  During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easilyaccessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritabledisease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics(NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA,techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a bloodsample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest.Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetalgene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict theinherited alleles with >98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy ofparental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robustmethod that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenicdisease with a prenatal diagnostic test based on a simple blood draw.

  Study EGAS00001002622

• Homozygous loss-of-function variants in European cosmopolitan and isolate populations

  Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown-as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.

  Study EGAS00001001606

• Exome sequences of AL amyloidosis (ALA), multiple myeloma (MM) and ALA+MM hematological malignancies

  DNA was isolated from aberrant plasma cells (aPCs) and peripheral blood of 12 ALA, 10 ALA+MM and 29 MM individuals. DNA from aPCs was amplified using REPLI-g Mini Kit (Qiagen). Totally, we analyzed 51 patients, 102 samples. One batch of exome libraries (paired tumor-normal samples from 12 ALA, 10 ALA+MM and 6 MM) was prepared using SureSelect Human All Exon V5 Kit (Agilent Technologies) and sequenced on Illumina HiSeq 4000 platform, 100 cycles. Second batch (23 MM samples; IDs ARK01-ARK26) was prepared using SureSelect Human All Exon V5 + IGH, IGK, IGL, MYC (Agilent Technologies) library preparation kit and sequenced on Illumina HiSeq 2000 platform in paired-end settings, 75 cycles. The reads were mapped using BWA-MEM on human genome GRCh38 without alternate loci.

  Dataset EGAD00001006047

• Singapore Adult Metabolism Study - Phase 2 (SAMS2)

  Singapore Adult Metabolism Study - Phase 2 (SAMS2) was an interventional study where hundreds of donors aged 21-45 were recruited to participate in a 16-week weight loss program. Study individuals selected (see below for more detailed selection standards) were sedentary (exercise 1 or fewer times a week), obese or overweight with a body fat mass greater than 24% and a BMI between 23-35 kg/m2. For this study, we adjusted BMI definition for Asian population, based on the WHO Consultation 2002, and the BMI cut-off is 23 kg/m2 for overweight and 27.5 kg/m2 for obese. The weight loss program included a combination of dietary interventions, structured exercise sessions, and additional physical activity performed in participants' own time. Energy and protein requirements were calculated based on each participant's weight, height, and physical activity level, with the goal of achieving a 40% calorie deficit. Participants' calorie intake was tracked using food recalls and questionnaires. Additionally, subjects attended structured exercise sessions at least three times per week, supervised by a coach. Each session consisted of 90 minutes of aerobic and strength training exercises, designed to burn approximately 500 kcal per session. To monitor daily physical activity, participants wore pedometers throughout the study. In total, the exercise sessions (500 kcal per session) and daily physical activity (targeting an additional 500 kcal) were aimed at achieving a total caloric expenditure of 2000 kcal per week. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average ~10% weight loss, accompanied by a ~30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific e/sQTLs were detected pre- and post- intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with GWAS identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

  Study phs004078