Search Results - EGA European Genome-Phenome Archive

Temporal stability of circulating microRNAs in human serum

Circulating microRNA biomarkers for disease have been subject to extensive research. However, insufficient consideration of variability in the healthy population has led to few markers achieving the performance necessary in independent follow-up studies to be taken forward to clinical practice. To investigate the natural variation of circulating microRNA over time, we performed small RNA sequencing in a longitudinal study of 66 women with no history of cancer, and determined the distribution and dynamics (via intraclass correlation coefficients, ICCs) of the miRNA profile over 3 time points sampled across 2-5 years. We also investigate abundances in circulation, as well as the impact of normalization, age, BMI, and other sample collection factors on microRNA measurements from small RNA sequencing.

Study EGAS00001003221

Effect of 28-day administration of Urolithin A to sedentary elderly on muscle gene expression

Urolithin A (UA) is a natural dietary, microflora derived, metabolite shown to stimulate mitophagy and improve muscle health in old animals and pre-clinical models of aging. UA was administered for 28-day in a first-in-human clinical trial to sedentary elderly subjects. Muscle biopsies were collected before the first dosing, and at the end of the 28-day period, under fasted conditions. Gene expression was measured by microarray. Gene-set enrichment analysis of the gene expression data showed that UA increased the transcription of mitochondrial related genesets. These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

Study EGAS00001003638

Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data. Our approach can be used to quantify the personal information contained within gut metagenome data.

Study EGAS00001007027

RNA sequencing on intestinal biopsies from inflammatory bowel disease patients treated with vehicle control, MEK inhibitor, or infliximab

By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Using a database of cellular signatures, we identified drugs that could modulate this pathway. To validate the anti-inflammatory activity of one class of small molecules ex vivo, we obtained biopsies from patients with active IBD and cultured these biopsies with a selective, non-ATP competitive MEK inhibitor (PD-0325901), infliximab (positive control), or DMSO (vehicle control) for 18 hours, then performed RNA sequencing.

Study EGAS00001007534

Somatic mutations and single cell transcriptomes reveal the root of malignant rhabdoid tumours

Like many childhood cancers, malignant rhabdoid tumours (MRT) are thought to arise from aberrant foetal development. Although MRT predominantly exhibit a mesenchymal phenotype, it has been suggested that the foetal root of MRT lies in neural crest development. Here, we combine phylogenetic analyses of MRT, single cell mRNA assays, and functional experiments in patient-derived MRT organoids, to define the embryological origin of MRT and explore therapeutic avenues that may drive MRT differentiation. Phylogenetic analyses from the distribution of somatic mutations revealed that MRT were related to neural crest-derived, but not to mesodermal tissues, providing direct evidence of the neural crest origin of MRT in humans. In MRT organoids, reversal of the principal driver event underpinning MRT, SMARCB1 loss, induced differentiation along mesenchymal pathways. Together, these findings placed MRT cells on a developmental trajectory of neural crest to mesenchyme conversion, and defined the transcriptional changes underpinning MRT differentiation. Searching perturbation databases for agents that mimic these mRNA changes, we identified HDAC and mTOR inhibition as potential differentiation agents. Treatment of MRT organoids with this drug combination induced proliferation arrest with transcriptional changes akin to SMARCB1 re-expression. Our study defines the embryological root of MRT and proposes a differentiation treatment for this often fatal childhood cancer.

Dataset EGAD00001006296

Molecular characterization of NASH-HCC

We collected 80 NASH-HCCs formalin fixed paraffin-embedded (FFPE) samples from 5 different institutions. NASH was diagnosed in FFPE samples by at least two expert pathologists following a described histological algorithm (Bedossa et al., Hepatology, 2012). All NASH patients included in the study were HBV- and HCV-negative. Patients reporting alcohol consumption ≥ 20 g/day for women and 30 g/day for men, as well as patients with a known liver disease superimposed to NASH were excluded. Tumour and paired non-tumour gDNA of NASH-HCC FFPE samples was submitted to Whole Exome Sequencing (WES). Exome capture and sequencing library preparation were performed using the SureSelect Human All Exon V5, no UTR hybridization capture kit from Agilent (Target Size 50 Mb). Libraries were sequenced on an Illumina HiSeq 4000 instrument with 100-bp paired-end reads.

Dataset EGAD00001007524

MutWP1: CRUK Grand Challenge Mutographs of Cancer: pancreas (2019-04-03)

The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute (Illumina HiSeqX, 40X and 20X depth respectively). Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2019-04-03.

Dataset EGAD00001004893

WGS and WTS data of patient diagnosed with HSTCL

WGS and WTS data of a single patient diagnosed with HSTCL. Whole-genome sequencing (WGS) was performed for the tumor-normal sample. Genomic DNA from tumor tissue was extracted with QIAamp DNA Mini Kit. The DNA for the matching normal was obtained from blood or buccal swabs and purified by Blood and Cell Culture DNA Mini kit or E.Z.N.A. Tissue DNA Kit (Omega Bio-tek) according to manufacturer’s instructions. The quantity and quality were assessed by Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen) and agarose gel electrophoresis. All sequencing libraries were prepared using TruSeq Nano DNA Library Prep Kit (Illumina). Paired-end sequencing was performed on Illumina HiSeq 4000 2x151 bp read length. Whole-transcriptome sequencing (WTS): Total RNA from snap frozen EITL tumor samples was extracted using TRIzol (Invitrogen) and purified with RNeasy Mini Kit (Qiagen) according to manufacturer’s instructions. The integrity of RNA was determined by electrophoresis using 2100 Bioanalyzer (Agilent Technologies). 500 ng of total RNA was reverse transcribed with iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA, USA). Quantification was performed using SsoFast EvaGreen Supermix and CFX96 Real-Time PCR System (both Bio-Rad). Sequencing libraries were prepared using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero (Illumina) and WTS was performed on Illumina HiSeq 2500 with 2x101 bp read length.

Dataset EGAD00001005229

MutWP1: CRUK Grand Challenge Mutographs of Cancer: Colorectal_LCM (2020-02-20)

The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, the International Agency for Research on Cancer is coordinating the recruitment of 5000 individuals with cancer (colorectal, renal, pancreatic, oesophageal adenocarcinoma or oesophageal squamous cancers) across 5 continents to explore whether different mutational signatures explain marked variation in incidence. In brief, through an international network of collaborators around the world, biological materials are collected, along with demographic, histological, clinical and questionnaire data. Whole genome sequences of tumour-germline DNA pairs are generated at the Wellcome Trust Sanger Institute. Somatic mutational signatures are subsequently extracted by non-negative matrix factorisation methods and correlated with risk factors data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2020-02-20.

Dataset EGAD00001005994

Test dataset: Sequence and variant data from public 1000 Genomes Project

This is a test dataset derived from public data of the 1000 Genomes Project. Its purpose is not to allow for any inference about cohort data or results, but to aid bioinformaticians in the technical development and testing of tools, as well as data consumers in learning how to access information. This dataset consists of 2508 samples from the 1000 Genomes Project (https://www.nature.com/articles/nature15393). Samples' (e.g. NA18534) data can be accessed through the IGSR portal (e.g. https://www.internationalgenome.org/data-portal/sample/NA18534) or their corresponding folder at the 1000 Genomes' FTP site (e.g. http://ftp.1000genomes.ebi.ac.uk/vol1/ftp/data_collections/1000_genomes_project/data/CHB/NA18534/exome_alignment/). There are several different types of data this dataset encompasses: Variant Calling Format (VCF, or its binary counterparts BCF) files, both joint (e.g. ALL_chr22_20130502_2504Individuals.vcf.gz) and split (HG01775.chrY.vcf.gz); exome sequencing CRAM files (e.g. NA18534.GRCh38DH.exome.cram); whole genome sequencing CRAM/BAM files (e.g. NA19239.cram). Additionally, there are multiple files that were sliced to create shorter files, which allows for a quick download, formated as "{FILE-INFO}__{NUMBER-OF-READS}r__{CHR}.{START-COORDINATE}-{END-COORDINATE}.{FILETYPE}" (e.g. "HG01500.GRCh38DH__90r__3.10000-10500__4.10000-10500.cram"). These files can be downloaded directly through the EGA-download-client PyEGA3 (https://github.com/EGA-archive/ega-download-client).

Dataset EGAD00001003338

Spatial heterogeneity of follicular lymphoma

Follicular lymphoma (FL) is an incurable B cell malignancy characterized by advanced stage disease and a heterogeneous clinical course. Recent genomic studies have focused on profiling “single” FL biopsies over several time-points, however, multi-site sampling in solid cancers has demonstrated profound spatial intra-tumor heterogeneity (ITH) with implications for precision medicine based initiatives. This study examined the extent of spatial heterogeneity in FL by whole exome sequencing 22 synchronously removed spatially separated biopsies from 9 patients. We observed significant differences in the extent of ITH across cases, with two distinct patterns of high and low spatial heterogeneity emerging. Site-specific alterations in genes with biological, prognostic or therapeutic relevance included, TNFRSF14, PIK3CD, TNFAIP3, PTEN, EP300 and XBP1. In depth characterization of these variants using deep-sequencing techniques confirmed their discordant nature, suggesting on-going genetic diversification driving evolution after widespread tumor dissemination. There was evidence of tumors comprising multiple competing subclones, with distinct clusters of mutations demonstrating differential expansions within spatially-separated sites. For cases where spatial tumors were examined at two time-points (FL and transformation to diffuse large B cell lymphoma (DLBCL)), the degree of heterogeneity increased with transformation. Collectively, our results demonstrate that spatial ITH is prevalent in FL. The existence of site-specific aberrations suggests that a single biopsy may not be sufficient in all patients to capture the full genomic complexity present and these spatial variations need to be considered in biomarker-led clinical studies.

Dataset EGAD00001003553

Exome trios in patients with gastroschisis (2019-04-08)

Gastroschisis (MIM 230750) is a herniation of the intestines through a defect of the abdominal wall lateral to the umbilicus (usually on the right side), and it is not covered by a membrane [Ledbetter, 2012]. Gastroschisis is a congenital anomaly with increasing incidence, easy prenatal diagnosis and extremely variable postnatal outcomes. On the basis of clinical manifestations, epidemiologic charateristics, and the presence and type of additional malformations, gastroschisis could be considered a heterogeneous condition with no gene/s discovered yet. This congenital anomaly affects approximately 1-3 infancts per 10,000 live births [Calzolari et al.1995;Parker et al.,2010] Current knowledge about causative mutations/variants. To date, no single gene has been linked to gastroschisis. Some publications have tried to link this malformation to variants in genes (such as AEBP1 (adipocyte enhancer binding protein) gene [Feldkamp et al,. 2012] or the VEGF-NOS3 pathway [Lammer et al., 2008]. Previously, a Scribble mutant mouse model (circletail) was reported to exhibit gastroschisis, however recent studies demonstrated that the Scribble knockout fetus exhibits exomphalos phenotype of gastroschisis [Carnagham et al., 2013]. 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/ . This dataset contains all the data available for this study on 2019-04-08.

Dataset EGAD00001004942

Spatial map of microglia states across CNS diseases

Microglia are the key immune cells involved in virtually all diseases of the central nervous system (CNS). Here, we generated a novel large-scale single-cell RNA-sequencing-derived taxonomy through the analysis of > 1 million CNS cells enriched for myeloid cells across > 15 different pathologies and conditions. Disease-associated human microglia, together with CNS-associated macrophages and monocytes, were differentiated iteratively into 27 superclusters and 192 clusters. This top-down approach, in combination with targeted and genome-wide subcellular spatial transcriptomics, enabled us to examine and compare the spatial interactome of the identified superclusters and clusters within and across pathologies. Our data provide new insights into the spatial dynamics of the endogenous CNS immune system during development, health and disease in humans.

Study EGAS50000001289

Peripheral blood DNA methylation of Crohn's disease patients starting treatment with adalimumab, vedolizumab or ustekinumab

In the current study we performed a longitudinal case-control study comparing the peripheral blood DNA methylome of Crohn's disease (CD) patients that were classified as responders and non-responders to adalimumab, vedolizumab, and ustekinumab. Patients with active CD were prospectively recruited and followed up for around 27 weeks into treatment during which response assessment took place. Response was defined as a strict combination of endoscopic- (≥50% reduction in SES-CD score) combined with either corticosteroid-free clinical- (≥3 point drop87 in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin reduction ≥50% or ≤5 g/mL and fecal calprotectin ≤250 µg/g).

Study EGAS00001007532

Neoantigen-Targeted CD8+ T-Cell Responses 1 With PD-1 Blockade Therapy

Background: The primary target of T-cell responses induced against cancer cells are peptides derived from non-synonymous mutations presented by HLA (neoantigens). However, the large diversity of HLA alleles and restricted availability of clinical samples have limited the study of the specificity and the evolution over time of the neoantigen-specific T cell responses induced after treatment with immune checkpoint blockade (ICB) immunotherapy. Methods: We applied a newly developed neoepitope-specific T cell isolation technology to perform a longitudinal landscape analysis of the neoepitope-specific T cells in peripheral blood and tumor from 11 patients with metastatic melanoma; 7 with response and 4 with no response to ICB. Briefly, first using computational prediction, the putative neoantigens in each patient were ranked based on affinity for the patient's HLA and expression levels. Then hundreds of barcoded capture reagents consisting of the patient HLA class I subtypes loaded with the corresponding predicted neoantigen were made and used to isolate neoepitope-specific T cells. Once isolated, the TCRs and the barcodes were sequenced. Finally, the tumor reactivity of the isolated neoepitope-specific TCRs (neoTCRs) was assessed upon co-culture of autologous melanoma cell lines from each patient with primary human T cells expressing the neoTCRs generated using a CRISPR-based non-viral gene editing to replace the endogenous TCRs. Results: The tumor mutation burden ranged between 3507 and 177 for patients with response to therapy and 977 to 31 for patients without response to therapy. We screened a median of 172 predicted neoantigen-HLA per patient across their 6 HLA molecules and isolated neoTCRs in all 11 patients. The number of mutations targeted ranged between 13 and 1. We assessed the neoTCR-tumor reactivity in samples from 3 patients with response and 3 patients without response. 39 of the 62 neoTCRs demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Multiple T cell clonotypes recognized a limited number of mutations in 7 patients with response (median of 41 different neoTCR clonotypes per patient), and the T cell specificities were recurrently detected in the blood and the tumor over time. Samples from 4 patients without response to therapy also demonstrated neoepitope-specific T cell responses in blood and tumor to a similarly restricted number of mutations, but lacked TCR polyclonality (median 6.5 neoTCR clonotypes per patient) and were not recurrently detected in sequential samples. Conclusion: Effective ICB therapy is associated with polyclonal neoepitope-specific T-cell responses in the tumor and blood that recognize a limited number of immunodominant mutations and are recurrently detected over time.

Study phs003153

Studies of Left Ventricular Dysfunction (SOLVD-BioLINCC)

Data Access NOTE:Please refer to the "Authorized Access" section below for information about how access to the data from this accession. Access differs from many other dbGaP accessions. ObjectivesThis study was initiated in 1986, primarily to evaluate the effects of enalapril, an ACE inhibitor, on long-term mortality and major morbidity in a group of participants with left ventricular dysfunction. Two large separate trials were run concurrently as part of SOLVD: 1) a prevention trial of participants with low ejection fraction but no overt symptoms of CHF and, 2) a treatment trial of participants with low ejection fraction and symptoms of CHF. In addition, participants at selected sites were entered into substudies to evaluate the effect of enalapril on a number of intermediate outcomes such as right and left ventricular function and hemodynamics, LV mass and wall stress, hormones, arrhythmias, exercise capacity, and quality of life in subsets of participants. Lastly, a registry of 6,336 participants with congestive heart failure of LV dysfunction was designed to describe the clinical course of an unselected group of participants. Background Congestive Heart Failure (CHF) is a major and increasingly recognized public health problem. The recognition that participants with CHF often have elevated peripheral vascular resistance has led to the introduction of vasodilator therapy, which has emerged as an important component of its treatment. Of the vasodilators, the angiotensin-converting enzyme (ACE) inhibitors appeared to be the most promising. In 1985, little was known about the impact of any long-term drug treatment on survival. SOLVD Registry: The SOLVD Registry is a hospital-based observational study, conducted at selected SOLVD hospitals, of participants with at least moderate left-ventricular dysfunction (EF ≤ 45%) and/or radiologically confirmed heart failure. It consists of a main study (n=6,273) and a substudy (n=898). Although there is overlap between the Registry and the SOLVD trials, the Registry sample is not a subset of SOLVD nor is it the pool of participants eligible for both trials. Participants A total of 2,569 participants were enrolled into the treatment study and 4,228 participants were enrolled in the prevention study. The dataset available through the NHLBI contains the prevention and treatment study data as well as the registry data. Conclusions In the prevention trial, a significant reduction in the incidence of heart failure and the rate of related hospitalizations was observed for participants in the enalapril arm. A statistically significant reduction in mortality was not observed in the enalapril treatment arm; however, there was a trend toward fewer total deaths and deaths due to cardiovascular causes among the enalapril participants (SOLVD Investigators, et al., 1992, PMID: 1463530).

Study phs003668

Genome-Wide Association Study of Leprosy and Dapsone Hypersensitivity Syndrome (DHS) in Chinese population

Leprosy GWAS (1) Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). Due to M. leprae's narrow host range and an inability to be cultured in vitro, the biological investigation of this disease has been difficult. Host genetic factors have been suggested to play an important role in disease development, but few have been identified. In this study, we attempted to identify the host genetic factors by performing a two-stage genome-wide association study (GWAS) in Chinese population. The initial genome-wide scan was done by genotyping 706 patients and 1225 controls using the Illumina HumanHap610 BeadChip, and the follow-up study was performed by genotyping 93 SNPs in three independent samples consisting of 3254 cases and 5955 controls. We identified significant association (P < 10-10) within six genes CCDC122 (13q14), C13orf31 (13q14), NOD2(16q12), TNFSF15 (9q32), HLA-DR (6p21) and RIPK2 (8q21), and suggestive association (P = 5.68x10-6) within LRRK2 (12q12). We also revealed suggestive evidence for C13orf31, LRRK2, NOD2 and RIPK2 to show stronger association in the multibacillary form than the paucibacillary form of leprosy. Our findings highlight the importance of the innate immune response, particularly NOD2-mediated signaling, in leprosy and suggests a new therapeutic target for leprosy. DHS GWAS Dapsone (DDS), as both an antibiotic and an anti-inflammatory agent, has been widely used for preventing and treating pathogen-caused infectious diseases and chronic inflammatory diseases. Currently, about 0.5-3.6% of individuals treated with DDS develop severe dapsone hypersensitivity syndrome (DHS) and the mortality rate is up to about 11-13%. However, until now, no tests are available to predict the risk of DHS. To identify the genetic risk factors of DHS, we performed a two-stage GWAS in Chinese population. In this study, the initial genome-wide scan was done by genotyping 39 DHS cases and 833 controls using Illumina Human 660W-Quad Beadchips and imputed human leukocyte antigen (HLA) molecules. Validation was performed by genotyping 24 SNPs using the Sequenom MassARRAY platform in additional 31 DHS cases and 1,089 controls through genotyping and 32 four-digit HLA-B alleles in an independent series of 37 DHS cases and 201 controls through Roche 454 sequencing. We identified significant association (OR =6.18, P = 3.84x10-13) with SNP rs2844573, which located between the HLA-B and MICA loci. HLA-B*13:01 was confirmed to be a strong risk factor for DHS (OR = 20.53, P = 6.84x10-25) and responsible for the association at rs2844573. The presence of HLA-B*13:01 had a sensitivity of 85.5% and specificity of 85.7% as a predictor for DHS, and its absence can reduce the risk by 7 fold (from 1.4% to 0.2%). HLA-B*13:01 is strongly associated with the development of DHS and can be used as a risk predictor of DHS in the individuals of Chinese and other Asian populations. Leprosy GWAS (2) This is a three-stage GWAS of leprosy in the Chinese population. The genome-wide discovery analysis involved two independent data sets: the new unpublished data set by genotyping 842 leprosy patients and 925 controls from northern and southern China using the Human660w-quad beadchips and a previously published GWAS data set of 706 leprosy cases, 1,225 healthy controls and 4,362 individuals with immune-related diseases as population controls from northern China of Chinese Han descent. Further validation studies were performed in two stages in a total of 6,765 cases and 9,505 controls from Chinese Han and minority descent in multiple areas of China, similar to the discovery stage. From this study, we discovered six new susceptibility loci with a combined P-value from discovery and validation stage surpassing genome-wide significance, including BATF3 at 1q32.3, CDH18 at 5p14.3, DEC1 at 9q32, EGR2 at 10q21.3, CCDC88B at 11q13.1 and CIITA at 16p13.13. Our current study has advanced the genetic understanding of leprosy by substantially increasing the number of confirmed genetic susceptibility loci. Leprosy GWAS (3) To discover additional leprosy susceptibility loci, we carried out a large-scale three-stage GWAS analysis of leprosy in Chinese population. The genome-wide discovery analysis (Stage 1) involved a new GWAS data set of 1,197 leprosy cases and 1,426 controls from northern and southern China conducted by using Illumina Omni Zhonghua chips with 900,015 single-nucleotide polymorphisms (SNPs), two published GWAS dataset (GWAS2 data set including 706 leprosy cases, 1,225 healthy controls genotyped by Illumina HumanHap610 beadchips, GWAS3 data set including 842 leprosy patients and 925 controls from northern and southern China genotyped by the Human660w-quad beadchips). Further validation studies were performed in two stages in a total of 5,413 cases and 9,771 controls from Chinese Han descent in multiple areas of China. In this study, we identified four novel associations at genome-wide significance (P < 5 x 10-8), all of which can indicate candidate genes within the susceptibility loci, SYN2 (3p25.2), BBS9 (7p14.3), CTSB (8p23.1) and MED30 (8q24.11), through a differential gene expression and eQTL analysis. Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy. Leprosy GWAS (4) In this study, we attempted to systematically investigate the contribution of protein-coding variants to leprosy susceptibility by performing a three-stage genome-wide association study (GWAS) of protein-coding variants in Chinese population. The initial genome-wide scan was done by genotyping 1,670 persons affected by leprosy and 2,321 controls using the Illumina Infinium Human Exome Beadchips (v1.0).The validation study was performed by genotyping 39 SNPs in an additional 3,169 leprosy patients and 9,814 healthy controls from the northern region of China, and the replication study was performed by genotyping eight SNPs in three independent samples from the southern regions of China consisting of 2,231 cases and 2,266 controls. We identified significant association (P < 1.23 x 10-6) within seven genes FLG (Gene ID: 2312), IL23R (Gene ID: 149233), CARD9 (Gene ID: 64170), NCKIPSD (Gene ID: 51517), TYK2 (Gene ID: 7297), SLC29A3 (Gene ID: 55315), IL27 (Gene ID: 246778). Our findings discover novel involvement of skin barrier and endocytosis/phagocytosis/autophagy, besides known innate and adaptive immunity, in the pathogenesis of leprosy, highlight the merits of protein coding variant studies for complex diseases. Here, the summary statistics from the five genome-wide association analyses were published.

Study phs000217

Pancreatitis after Treatment for Acute Lymphoblastic Leukemia (SJIRB XPD04-123 and XPD05-078)

A complication of acute lymphoblastic leukemia (ALL) treatment is acute pancreatitis, which is one of the common causes of asparaginase intolerance. To determine clinical and genetic risk factors for pancreatitis, we studied a cohort of children and young adults with ALL enrolled on COG trials (9904/9905/9906, AALL0232) and on St. Jude trial Total XV. We performed a genome-wide association study using germline DNA collected from blood in patients at remission in this cohort of 5185 patients and in an independent case-control group of 213 patients on AALL0331. The frequency of pancreatitis in the cohort was 2.3% (117 of 5185). No common variants reached genome-wide significance, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (odds ratio = 587, 95% confidence interval 66.8-5166, P = 9.0 x 10-9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = 0.018). Sixteen CPA2 SNPs were associated (P < 0.05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biological functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation.

Study phs001350

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

WXS and RNA-seq for 22 patients treated with radiation + immunotherapy

Over 500 active clinical trials are investigating combination radiation (RT) and immune checkpoint blockade (ICB) as a cancer treatment; however, the majority of trials have found no positive interaction. We performed a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative RT and ICB. Concurrent treatment was superior to sequential treatment in augmenting local and distant tumor responses and improving overall survival in a subset of patients with highly aneuploid tumors, but not in those with less aneuploid tumors. Our analysis suggested that concurrent treatment eliminated immunologically cold aneuploid tumors better than sequential treatment and improved patient outcomes. In addition, we report that RT alone decreased intratumoral cytotoxic effector T cell and adaptive immune gene expression signatures, in contrast to upregulation of key immune pathways after concurrent administration of RT and ICB. Our findings distinguish the differential genomic and transcriptomic effects of RT versus RT and ICB and challenge the prevailing paradigm that local ablative RT beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a novel biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with RT and ICB.

Study EGAS00001006212

Integrated genomic analysis for HCC

Liver cancer is a common malignancy and is the third cause of cancer-related death in the world and hepatocellular carcinoma (HCC) is the major type of liver cancer, accounting for ~90% of cases. Only 20 ~ 30% of patients can benefit from combined immunotherapy and targeted therapy due to the high inter-tumor heterogeneity of HCC. This work aims to identify homogeneous and robust molecular subtypes in HCC based on a large, homogenous and well-annotated cohort. We performed whole genome/exome sequencing (WGS/WES) and/or RNA sequencing (RNA-seq) on 529 HCC from 461 patients collected mainly in France. Based on the great consistence between genomic and transcriptomic data, we identified 9 robust HCC subtypes mainly based on driver mutations. And we further characterized HCC subtypes using genomic, transcriptomic and clinicopathological features. Among 9 subtypes, 5 subtypes belonged to chromosome instable tumors, while 3 subtypes belonged to chromosome stable tumors. In addition, our subtypes were associated with prognosis and we also found different distributions of subtypes across various features, such as etiology and gender. Our study provided a robust molecular classification based on a large HCC dataset from Western country, it improves our understanding of the mechanisms of carcinogenesis and will facilitate development of genome-based precision medicine in HCC.

Study EGAS00001007957

PSCP_bisulphite analysis in hESCs

Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. 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 EGAD00001002235

RNA-seq analysis of transcriptome variation with human ESC subclones

Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny 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 EGAD00001004266

PSCP_mutation analysis in hESCs

Many studies over the past 10 years, culminating in the recent report of the International Stem Cell Initiative (ISCI, 2011) have shown that hPSC acquire genetic and epigenetic changes during their time in culture. Many of the genetic changes are non-random and recurrent, probably because they provide a selective growth advantage to the undifferentiated cells. Some are shared by embryonal carcinoma cells, the malignant counterparts of ES cells. The origins of these growth advantages are poorly understood, but may come from altered cell cycle dynamics, resistance to apoptosis or altered patterns of differentiation. Less is known about the nature and consequences of epigenetic changes, but it is likely that these similarly affect hPSC behaviour; e.g., enhanced expression of DLK1, an imprinted gene, is associated with altered hPSC growth (Enver et al 2005). Inevitably, these genetic and epigenetic changes will impact on our ability to use hPSC for regenerative medicine, either because malignant transformation of the undifferentiated cells or their differentiated derivatives to be used for transplantation compromises safety, or because they impede the function of those differentiated derivatives, or because they affect the efficiency with which the undifferentiated cells can be expanded and differentiated into desired cell types. Focusing initially upon the existing clinical grade hESC lines, later moving to iPSC, we will Consolidate and extend knowledge of the rate, type and functional impact of the genetic variations that occur during hPSC culture. We will use whole genome and exome sequencing as well as SNP arrays, together with clonal analysis and other cytogenetics techniques. Common changes will be compared with those found in the normal human population, at low frequency in the original cell population or observed during iPSC generation in the HIPSCI project currently based at the WTSI. These studies will provide a better understanding of the range of genetic changes that occur in hPSC beyond the CNVs already identified. In conjunction with cancer genome resources and expertise at WTSI, bioinformatic analyses of these hPSC data will allow us to assess potential impact on hPSC behaviour pertinent to applications in regenerative medicine, notably the likelihood that specific changes arising in undifferentiated PSC cultures may be associated with potential malignant transformation of differentiated progeny. This data is part of a pre-publication release. For information on the proper use of pre-publication data shred by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset EGAD00001002231

Multiple Myeloma Genomic Study (MMGS)

Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow (BM) infiltration and lytic bone lesions. Recent studies of massive parallel sequencing of tumor cells obtained from the BM of patients with MM have demonstrated significant clonal heterogeneity in MM. Despite this remarkable clonal heterogeneity, it could be envisioned that such clonal diversity may be even higher since single BM samples only represent a small fraction of the whole BM compartment, and the pattern of BM infiltration in MM is typically patchy. In addition, BM biopsies are painful and cannot be repeated multiple times during the course of therapy, indicating a need for less invasive methods to molecularly characterize MM patients and monitor disease progression during the therapy. Thus, optimal characterization of circulating tumor cells (CTCs) may represent a non-invasive method to capture relevant mutations present in PC clones. In addition, MM almost always progresses from precursor states of monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) to overt MM. However, some patients rapidly progress from MGUS/SMM to overt MM (progressors) with a rate of progression of up to 70% over 5 years, while others remain indolent with minimal progression over the same time period (non-progressors). Although many patients are diagnosed with earlier phases of disease, most patients do not receive treatment until their disease progresses, at which time they have overt end-organ damage. This concept of initiating therapy at the time of symptomatic disease is analogous to initiating therapy in patients with solid tumors only after the development of measurable metastatic disease. It is therefore not surprising that cure is not achieved for most patients with MM. Interestingly, studies have demonstrated that MGUS/SMM clones may already harbor chromosomal alterations (Ig loci or hyperdiploidy) and that progression to MM is mainly due to expansion of clones that were already present in the early stages of MGUS/SMM. However, the biological factors that discriminate progressors from non-progressors in MGUS/SMM are not well known. Therefore, our overarching hypothesis is that an effective therapeutic intervention will result from defining genomic and transcriptomic markers that are associated with disease progression. We believe, therefore, that focused research studies that define molecular mechanisms of clonal evolution in MGUS/SMM/MM will identify novel biomarkers of disease progression and help develop therapeutic agents that prevent or delay progression from MGUS to overt MM. Indeed, by eradicating the disease at the precursor stages, MM may become a preventable disease. Recently, a new term called Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been proposed to describe asymptomatic individuals with hematologic malignancy-associated somatic mutations. Those individuals do not fulfill any diagnostic criteria for any hematological malignancy yet they have a tendency to progress into myelodysplastic syndrome (MDS) or myeloid or lymphoid neoplasia at a rate of around 0.5-1% per year, similar to MGUS. The frequency of CHIP and role of HSCs mutations in enhancing acquisition of somatic mutations in MM plasma cells, allowing progression following treatment, has not been studied. Investigating the dysregulated pathways in early progenitor cells would allow us to understand the reasons of progression and establish novel therapeutic and potentially preventive strategies. This study dissects genomic and transcriptomic characteristics of clonal evolution from MGUS/SMM to MM as well as the characteristics of the tumor microenvironment/immune cells/peripheral blood. Our hypothesis is that molecular biomarkers will be strong predictors of progression from MGUS/SMM to MM and will allow for the development of novel therapeutic agents that prevent or delay this progression. We aim to define genomic and transcriptomic markers that lead to progression from MGUS/SMM to MM in tumor cells, blood biopsies (cell free DNA and circulating tumor cells), and the tumor microenvironment.

Study phs001323

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