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• Genomic Evolution of Breast Cancer Metastasis and Relapse

  Recurrent breast cancer is almost universally fatal. We characterize 170 patients locally relapsed or distant metastatic cancers using massively parallel sequencing. We identify that the relapse-seeding clone disseminates late from the primary tumor. TP53 and AKT1 appear to be enriched in ER-positive cancers predisposed to relapse. Mutation acquisition continues at relapse as the same mutation signatures continue to operate and new signatures, such as that caused by radiotherapy appear de novo. In 49% of cases we identify drivers mutations private to the relapse and these are sampled from a wider range of cancer genes, including SWI-SNF complex and JAK-STAT signaling.

  Dataset EGAD00001002696

• Bulk-tissue RNA-sequencing paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control individuals ( anterior prefrontal cortex & cerebellar cortex – 4 individuals, putamen- 3 individuals)

  Profiling of paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen samples by bulk-tissue RNA-sequencing. Samples were derived from 4 post-mortem neuropathologically-confirmed control individuals ( anterior prefrontal cortex – 4 individuals, cerebellar cortex – 4 individuals, putamen- 3 individuals). Paired-end FASTQ files for each of the human samples are provided. Fastp (v 0.20.0), a fast all-in-one FASTQ pre-processor, was used for adapter trimming, read filtering and base correction. Fastp default settings were used for quality filtering and base correction. Further details on parameters used are available here: https://github.com/RHReynolds/RNAseqProcessing .

  Dataset EGAD00001009264

• Lung cancer organoids

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term culture conditions of human airway epithelial organoids that contain all major cell populations and allow personalized human disease modelling. We collected macroscopically inconspicuous lung tissue from non-small-cell lung cancer (NSCLC) patients undergoing medically indicated surgery and isolated epithelial cells to engineer 3D organoids. We exploit the potential to derive sub-clones from AOs to demonstrate the feasibility of CRISPR gene editing. Finally, we show that AOs readily allow modelling of viral infections such as RSV and for the first time demonstrate the possibility to study neutrophil-epithelium interaction in an organoid model. Taken together, we anticipate that human AOs will find broad applications in the study of adult human airway epithelium in health and disease.

  Dataset EGAD00001004013

• Complete DNA/RNA sequencing dataset for Australian ICGC ovarian cancer sequencing project 2014-07-07

  Complete WGS and RNA-Seq dataset for Australian ICGC ovarian cancer sequencing project 2014-07-07, representing 93 donors. Sequencing was performed on Illumina HiSeq. Alignment of the lane-level fastq data was performed with bwa (WGS data) and RSEM (transcriptome data). For this dataset lane-level .bam files have been merged and de-duplicated to create a single bam file for each sample type (tumour/normal) for each donor. This dataset supersedes all previous datasets for this study. 2016-08-08 updated with 14 outstanding RNA-seq samples & corresponding RSEM bams 2016-12-07 updated with 7 outstanding RNA-seq controls and corresponding RSEM bams

  Dataset EGAD00001000877

• Whole exome sequencing for clarification of rare causes of axonal Charcot-Marie-Tooth disease (2017-08-16)

  The project is focused on the axonal forms of Charcot-Marie-Tooth (CMT) disease. We have selected 13 families (7 from Spain and 6 from Czech Republic) that have been indepth clinically assessed and previously tested for mutations in known CMT genes without causal variants characterised. In these patients we expect to discover several CMT2 genes. Thus, we requested for exome sequencing of 45 DNAs:27 exomes in families from Spain and 18 exomes in the families from Czech Republic. 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 2017-08-16.

  Dataset EGAD00001003565

• BAM files: Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D)

  cDNA depleted RNA (500ng total RNA input) was fragmented to 150-200 nucleotides in first strand buffer for 3 minutes at 94°C. Random hexamer primed first strand was generated in presence of dATP, dGTP, dCTP and cTTP. Second strand was generated using dUTP instead of dTTP to tag the second strand. Subsequent steps to generate the sequencing libraries were performed with the KAPA HTP Library Preparation Kit for Illumina sequencing with minor modifications, i.e., after indexed adapter ligation to the dsDNA fragments, the library was treated with USER enzyme (NEB_M5505L) in order to digest the second strand derived fragments. After amplification of the libraries, samples with unique sample indexes were pooled and sequenced paired-end 2x50bp on a HiSeq2500 system following standard Illumina guidelines.

  Dataset EGAD00001003806

• Exome sequencing of thyroid disease in Val Borbera

  The Val Borbera is a region characterized by low iodine and high prevalence of thyroid disorders, the commonest endocrine disorders in the general population. About 30% of the participants of the Val Borbera Project were affected by such disorders and were characterized by several parameters, TSH level, anti TPO antibodies, echography, family origin. Individuals with extreme phenotypes were identified and could be clustered based on family origin and genotype. We propose to exome sequence 6 of them, affected with true goiter, at high dept (40-60x) to obtain information on exonic rare variants. Due to the family structure and to the availability of whole genome sequence information on 110 individuals from the isolated population we expect to be able to identify putative causative variants for thyroid disorders that may be studied in the remaining affected individuals.

  Dataset EGAD00001000729

• Shallow whole genome sequencing

  This dataset contains a collection of tumour samples from high grade serous ovarian carcinoma patients with recurrent disease collected near the point of diagnosis as well as tumour samples collected after patient relapse upon or some time after study entry. The majority of diagnosis samples were preserved in neutral buffered formalin whereas the majority of post-relapse samples were preserved in universal molecular fixative (UMFIX, Sakura Finetek USA, Inc). DNA was extracted and whole genome sequencing libraries were prepared either using the TruSeq DNA Nano kit (Illumina) or the ThruPLEX DNA-Seq Kit (Takara Bio), which were respectively sequenced at low depth (~0.1-0.5X) on illumina HiSeq 2500 and HiSeq 4000 sequencing platforms. Sequenced reads were aligned to the GRCh37 reference genome (release hs37d5).

  Dataset EGAD00001011049

• single-cell RNA-seq Case-Control study of children progressing to Type1 diabetes

  It was a single-cell RNA sequencing study on the PBMC samples from four Finnish children at risk of developing Type 1 diabetes and their gender age and HLA matched control children. All four Case children were positive for multiple islet specific autoantibodies and two of them also progressed to clinical disease during the follow up whereas the control children remain negative for all autoantibodies. Single-cell analysis confirmed some of the signatures obtained from the bulk data. It identified that high IL32 in case samples in the bulk RNA-seq was contributed mainly by activated T cells and NK cells. Trajectory analysis of the scRNA-seq data suggested that IL32 expression increased as the T cells moved towards activated state.

  Dataset EGAD00001005768

• RNA-seq BAM files from newborn screening dried blood spot samples

  Paired-end RNA-seq BAM files from 21 newborn screening dried blood spot (DBS) samples. These DBS samples were obtained from extremely low gestional age newborns, where 10 of them were affected by a fetal inflammatory response (FIR) before birth, and 11 were unaffected. Total RNA was sequenced using an Illumina NextSeq-500 instrument. The sample preparation protocol included the depletion of rRNA and globin mRNA using the Globin Zero Gold rRNA Removal Kit from Illumina. Libraries were prepared using the NebNext Ultra TM II Directionl RNA LIbrary Prep Kit (New England Biolabs). There is one BAM file per sample and there is an additional BAM file, corresponding to sample BS13, which was downsampled to 1/4 of its original depth (see BS13_README file for details).

  Dataset EGAD00001005009

• Genome Diversity in Africa Project - ancient samples - standard libraries

  Given the central importance of Africa to studies of human origins, genetic diversity and disease susceptibility, large-scale and representative characterisation of genetic diversity in Africa is needed. Analyses of ancient DNA from Africa would complement sequencing of modern African populations and provide unique opportunities to transform our understanding of the pre-history of the region. This approach would greatly refine our understanding of population structure and gene flow in Africa and globally, including genetic signatures of ancient admixture. This low coverage sequencing experiment will allow us to test and refine our pipeline for ancient DNA sequencing. 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 EGAD00001002211

• The Transcriptional Landscape of SHH Medulloblastoma

  To further understand the biology of Sonic hedgehog medulloblastoma and its molecular subtypes, we studied 250 human Shh-MB using strand-specific RNA sequencing. We identified novel alterations within the cAMP dependent pathway and found that 18% of tumors have genetic events that directly target the abundance and/or stability of MYCN. We also discovered an extensive network of fusions in focally amplified regions, and several loss-of-function fusions in tumor suppressor genes PTCH, SUFU and NCOR1. Molecular convergence on a core of specific genes by nucleotide variants, copy number aberrations, and gene fusions highlights key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma.

  Dataset EGAD00001006305

• The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization

  To elucidate the epigenetic changes which occur when human long-term hematopoietic stem cells (LT-HSC) become activated we performed Bulk ATAC-Seq on 13 sorted bulk hematopoietic populations from cord bloodas well as single-cell ATAC-Seq upon CD34+CD38-CD45RA- cells enriched for HSC as well as CD34+/CD38+ progenitor cells both from cord blood. These studies revealed gains of chromatin accessibility around CTCF binding sites during HSPC activation, as such we additionally performed Low-C to directly profile the 3D conformation of human cord-blood derived LT-HSC and Short-term hematopoietic stem cells (ST-HSC), as well as Hi-C , ATAC-Seq and CTCF ChIP-Seq upon the OCIAML-2 cell line in which CTCF sites gained during LT-HSC activation are enriched. Finally we transduced human cord-blood LT-HSC with an shCTCF vector; in-vitro cultured LT-HSC cells harbouring shCTCF were used to perform RNA-Seq, and scATAC-Seq was performed on CD34+/CD38- human CB cells transduced with shCTCF, four weeks post xeno-transplantation into mice. Collectively these studies have helped us demonstrate the role of 3D chromatin conformation changes during human LT-HSC activation.

  Dataset EGAD00001006447

• CIDR: NCI Genome Wide Predictors of Survival in Colorectal Cancer

  CIDR/Molecular Correlates: This study genotyped archived blood samples from colorectal cancer cases participating in clinical trials. The goals of this project were to identify genetic variants associated with survival outcomes treatment and treatment-related severe adverse events among patients with colorectal cancer. Another goal was to examine the impact of adding information on germline genetic loci to existing prognostic models. MOSAIC: Multicenter International Study of Oxaliplatin/ 5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC). A randomized, open label efficacy trial to evaluate the FOLFOX regimen versus LV5FU2 in the adjuvant treatment of stage II and III colon cancer. The primary end point was disease-free survival. CPT.ES1.604: Randomized phase 3 study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic CRC. The aim of this study was to demonstrate that a regimen without leucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI (response rate). 03-TTD-01: The purpose of this phase III, multicenter, randomized, open-label study is to evaluate the safety and efficacy of combination therapy with capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer. The primary outcome measure is time to disease progression. Secondary outcome measures are to determine safety of combination, objective response rate, time to onset of response, duration of response, time to treatment failure, one year survival time, and overall survival time. 03-TTD-01: The purpose of this phase III, multicenter, randomized, open-label study is to evaluate the safety and efficacy of combination therapy with capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer. The primary outcome measure is time to disease progression. Secondary outcome measures are to determine safety of combination, objective response rate, time to onset of response, duration of response, time to treatment failure, one year survival time, and overall survival time. N0147: Randomized phase III clinical trial for adjuvant therapy in stage III colon cancer patients enrolled at institutions across North America. Originally designed to compare three different chemotherapy regimens, and then later expanded to evaluate adding cetuximab to each original arm (leading to six total arms). Further modification later added pre-screening for KRAS mutation status, with the resulting goal to assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. Main outcome of interest is disease-free survival in patients with wild-type KRAS, while secondary end points included overall survival and toxicity. N9741: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients who have advanced, recurrent, or metastatic colorectal cancer that cannot be treated with surgery or radiation therapy. C-08: A Phase III Clinical Trial Comparing Infusional 5-Fluorouracil (5-FU), Leucovorin, and Oxaliplatin (mFOLFOX6) Every Two Weeks With Bevacizumab to the Same Regimen Without Bevacizumab For the Treatment of Patients With Resected Stages II and III Carcinoma of the Colon. The primary aim of the trial was to compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging disease-free survival and the secondary aim was to compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging survival.

  Study phs001290

• National Institute of Dental and Craniofacial Research (NIDCR) Sjögren's International Collaborative Clinical Alliance (SICCA): Center for Inherited Disease Research (CIDR) Genome-Wide Genotyping

  The Sjögren's International Collaborative Clinical Alliance (SICCA) is a multisite observational cohort study that recruited a large cohort of geographically diverse participants. Enrollment of participants began in late 2004 at five (one domestic and four international) sites, in which all groups used the same protocol-directed methods to provide uniform evaluations; collect oral, ocular, and rheumatologic data; and collect specimens. The sites were located at the University of Buenos Aires, Argentina; Peking Union Medical College, Beijing, China; Rigshopitalet (formerly at Glostrup Hospital), Copenhagen, Denmark; Kanazawa Medical University, Ishikawa, Japan; King's College, London, UK (joined in 2007); and the University of California, San Francisco (UCSF). In 2009, Aravind Eye Hospital, Madurai, India; Johns Hopkins University, Baltimore, MD; and University of Pennsylvania, Philadelphia, PA were added as additional SICCA sites. UCSF is the coordinating center for SICCA. All specimens and data collected for SICCA are housed at UCSF. To facilitate the research focused on understanding the genetics of Sjögren'sSjögren's syndrome, high-density SNP genotype data and SICCA clinical information are being made available to the research community. This includes participants recruited from all SICCA research groups (RG). These participants (3,382), blood relatives (439), and unrelated healthy controls (25) had their whole blood or saliva sample (Oragene) extracted for DNA for the GWAS at the UCSF DNA Bank. Eighty eight percent of the participants are women, most are of European or Asian ancestry and the median age is 55. To assess potential batch effects when doing case-control comparisons using planned external controls, 30 DNA samples from each of three studies were genotyped with SICCA DNA samples: The Genetic Architecture of Smoking and Smoking Cessation - Collaborative Genetic Study of Nicotine Dependence (COGEND) - PI: Laura Bierut. NEI-Age-related disease study (AREDS) - Genetic Variation in Refractive Error Substudy - PI: Dwight Stambolian. Controls from the National Institute of Mental Health's (NIMH's) Human Genetics Initiative. Genome-Wide Association Study of Schizophrenia - PI: Pablo V. Gejman. Molecular Genetics of Schizophrenia - nonGAIN Sample (MGS_nonGAIN) - PI: Pablo V. Gejman. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data quality control, dbGaP preparation and posting, and imputation to 1000 Genomes to increase SNP density was performed by the Center for Biomedical Statistics at the University of Washington. Data analysis was performed at UCSF using software PLINK, EIGENSOFT, and SNPTEST.

  Study phs000672

• Genetics of Human Inherited Retinal Diseases (GHIRD)

  The goal of this project is to identify novel mutations and genes involved in human retinal disorders, a stated priority of the National Eye Institute. To accomplish this, additional genes whose mutations cause inherited retinal diseases (IRD) will be identified by combining targeted gene panel sequencing, whole exome sequencing, and whole genome sequencing. We have collected about 1050 patient families around the world. In this proposal, we will identify the underlying mutations in these patients using a combination of targeted gene panel sequencing, whole exome sequencing, whole genome sequencing, bioinformatics, statistics, and functional studies. Genes targeted for gene panel sequencing are: ABCA4; ASIC2; JAG1; ABCC6; ARL3; ATP1B2; BBS1; BBS2; BBS4; OPN1SW; CAPN5; C21orf2; CA4; CACNA1F; CDH3; CHM; ERCC8; CLCN2; CLCN3; CLCN7; TPP1; CLN3; CLN5; CNGB1; CNGA1; CNGA3; COL2A1; COL9A1; COL11A1; CRX; VCAN; CTSD; TIMM8A; DMD; CLN8; ERCC6; EFEMP1; OPN1MW; GNAT1; GNAT2; GNGT1; GRM6; GUCA1A; GUCA1B; GUCY2F; GUCY2D; HARS; CFH; HK1; IDH3B; IMPDH1; IMPG1; KCNJ13; KIF11; LRP5; MAK; MITF; TRPM1; MTTP; MVK; MYO7A; NDP; NEK2; NEUROD1; NPHP1; NRL; OAT; OPA1; OTX2; PAX2; PAX6; PDCL; PCYT1A; PDE6A; PDE6C; PDE6G; PDE6H; PDE6B; PEX1; PEX6; PEX7; PEX10; PEX12; PEX13; PEX14; PFDN5; PGK1; PHYH; PIN1; PLA2G5; PPT1; PRKCZ; PEX19; PEX2; PEX5; RB1; RBP3; RBP4; OPN1LW; RDH5; PRPH2; RGR; RHO; GRK1; RLBP1; ROM1; RP9; RP1; RP2; RPGR; RPE65; RS1; SAG; ATXN7; CCL2; SLC6A6; ELOVL4; TEAD1; NR2F1; TIMP3; NR2E1; TTPA; TUB; TULP1; UCHL3; USH2A; CLRN1; VLDLR; BEST1; WFS1; ALMS1; MKKS; FZD4; OFD1; PEX3; CTSF; GBF1; ADAM9; RGS9; PEX11B; PROM1; UNC119; PRPF4; PRPF3; AIFM1; SLC24A1; LRAT; ASIC3; RAB28; PEX16; ITM2B; SLC4A7; IQCB1; CROCC; IFT140; DHX38; MFN2; NR2E3; USH1C; TOPORS; MERTK; FBLN5; CIB2; PRPF8; SDCCAG8; IFT27; TREX1; RRAS2; CEP164; ATF6; TRIM32; RIMS1; SNRNP200; CLUAP1; EMC1; ZNF423; TTLL5; AGTPBP1; RPGRIP1L; CRB1; TSPAN12; ARL2BP; AIPL1; PRPF6; FSCN2; ABHD12; PRPF31; TCTN3; IFT172; CNNM4; NPHP3; INVS; BBS9; FLVCR1; RDH8; IMPG2; WDPCP; RDH11; TMEM216; TMEM138; LZTFL1; CNGB3; AHI1; MKS1; CLN6; BBS7; POMGNT1; PEX26; SPATA7; KIZ; KLHL7; INPP5E; MDM1; CABP4; RPGRIP1; MCOLN1; CC2D2A; KIAA1549; SLC7A14; WDR19; NYX; CDH23; SEMA4A; MPP5; NMNAT1; TMEM237; PCDH15; C5orf42; GNPTAB; TMEM231; TCTN1; SRD5A3; BBS10; ZNF408; TTC21B; CSPP1; LPCAT1; DHDDS; PDZD7; PANK2; CEP290; OPA3; DNAJC5; PITPNM3; MFRP; HMCN1; ADGRV1; ARL6; FAM161A; TMEM126A; GNPTG; GJA10; RAX2; TUBGCP6; TMEM67; ACBD5; C12orf65; CDHR1; BBIP1; REEP6; CACNA2D4; RP1L1; CEP41; C1QTNF5; NXNL1; TTC8; USH1G; BBS5; ZNF513; RDH12; SLC38A8; C8orf37; VPS13B; NXNL2; BBS12; ADGRA3; LCA5; KCNV2; ADAMTS18; ARL13B; ATOH7; MFSD8; NPHP4; CCDC66; CYP4V2; CRB2; RD3; LRIT3; EYS; KIF7; CERKL; RGS9BP; C2orf71; GDF6; DTHD1; GPR179; CISD2; CCR2; PRCD; WHRN; ADGRA3. The current dbGaP study release makes available all sequencing-derived vcf data of study participants.

  Study phs001517

• Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway

  Although cancer-associated fibroblast (CAF) heterogeneity is well-established, the impact of chemotherapy on CAF populations remains poorly understood. We address this question in high-grade serous ovarian cancer (HGSOC), in which we previously identified 4 CAF populations. While the global content in stroma increases in HGSOC after chemotherapy, the proportion of FAP+ CAF (also called CAF-S1) decreases. Still, maintenance of high residual CAF-S1 content after chemotherapy is associated with reduced CD8+ T lymphocyte density and poor patient prognosis, emphasizing the importance of CAF-S1 reduction upon treatment. Single cell analysis, spatial transcriptomics and immunohistochemistry reveal that the content in the ECM-producing ANTXR1+ CAF-S1 cluster (ECM-myCAF) is the most affected by chemotherapy. Moreover, functional assays demonstrate that ECM-myCAF isolated from HGSOC reduce CD8+ T-cell cytotoxicity through a Yes Associated Protein 1 (YAP1)-dependent mechanism. Thus, efficient inhibition after treatment of YAP1-signaling pathway in the ECM-myCAF cluster is required to enhance CD8+ T-cell cytotoxicity. Altogether, these data pave the way for novel therapy targeting YAP1 in ECM-myCAF in HGSOC.

  Study EGAS50000000136

• DNA Methylation Markers and Pancreatic Cancer Risk in 3 Cohort Studies (NHS, PHS, HPFS)

  Pancreatic cancer is the 4th leading cause of cancer deaths in the US. Due to the lack of early symptoms, pancreatic cancer is difficult to identify at early stages and no screening is available for the general population. Identifying pancreatic cancer at earlier stages could significantly improve survival with increased opportunities for surgery. New high-dimensional arrays designed to measure DNA methylation levels at hundreds of thousands of CpG sites throughout the genome have opened opportunities to examine the role of DNA methylation in cancer risk using blood samples. Using this method, archived samples from prospective studies can be used to examine early changes in the DNA methylation levels in individuals who develop cancer months or years later, providing new opportunities to better understand biological mechanisms and, perhaps, identify biomarkers for early detection. Pancreatic cancer cases and matched controls were obtained from 3 large cohort studies, the Nurses' Health Study (NHS), the Physician's Health Study (PHS), and the Health Professionals Follow-up Study (HPFS), to measure DNA methylation in stored buffy coats using a nested case-control study design.

  Study phs001917

• Rare Disease Susceptibility Variant Study in Children with Crohn's Disease and Their Parents Using Targeted Gene Sequencing.

  We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn's disease, including 179 parent-child trios and 200 controls, both of European ancestry. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn's disease. (Reprinted from G3 2018;8(9): 2881-2888; PMID: 30166421. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

  Study phs001751

• Circulating RNA profiles of healthy and preeclamptic pregnancies

  This prospective study investigated whether circulating RNA (C-RNA; cell free RNA present in the bloodstream) measurements could non-invasively monitor pregnancy status, with emphasis on detecting molecular markers associated with preterm preeclampsia. Whole blood samples were collected from pregnant women at the time of diagnosis with early-onset preeclampsia with severe features. Blood samples were also obtained normotypical control pregnancies and from patients diagnosed with late-onset preeclampsia for comparison. For all samples, C-RNA was extracted from 4 mL blood and whole transcriptome enrichment performed on cDNA libraries prior to sequencing to a target depth of 50M reads on an Illumina HiSeq 2000 platform. Throughout the course of this work, whole transcriptome RNA sequencing data was obtained from 289 C-RNA samples collected from 178 subjects. The complete dataset consists of samples from the following cohorts: Illumina Preeclampsia Cohort (iPEC): 40 pregnancies at the time of early-onset preeclampsia diagnosis and 73 gestational age-matched controls PEARL preeclampsia cohort: 12 early-onset and 12 late-onset preeclampsia patients PEARL healthy control cohort: 152 longitundinal samples collected from 41 healthy pregnancies

  Study phs002017

• Epigenomes and Transcriptomes of Brain Samples of Schizophrenics and Controls

  We examined the effects of antipsychotic medications on the cell-specific epigenomics and transcriptomics in the frontal cortex of schizophrenic subjects. We performed ChIP-seq (H3K4me3 and H3K27ac) and RNA-seq on neuronal and non-neuronal nuclei of postmortem frontal cortex samples from two cohorts of schizophrenics, either previously treated or not with antipsychotic medications, and control subjects individually matched by sex and age. In total, we tested 29 schizophrenics (15 untreated and 14 treated patients) and their matched control samples. Two replicates were produced on each brain sample for each assay. ChIP-seq data were generated using MOWChIP-seq (Zhu et al., PMID: 31666743) and RNA-seq data were produced using the combination of SMART-seq2 (Picelli et al., PMID: 24385147) and a Nextera XT DNA library preparation kit. The filename contains the information on the experimental group, the number of the sample within the group, the type of the brain nuclei, the epigenomic/transcriptomic data set (either H3K27ac or mRNA), and the number of replicate. For example, “SCZ-1-untreated-neuron-H3K4me3-R1” refers untreated schizophrenic sample #1, replicate 1 ChIP-seq data on H3K4me3.

  Study phs002487

• Clonal Evolution and Transcriptomic Analysis of Chronic Lymphocytic Leukemia Treated with Ibrutinib

  Disease progression has been increasingly appreciated with the use of ibrutinib to treat chronic lymphocytic leukemia (CLL). Understanding the pattern of clonal evolution and transcriptomic changes during the early treatment period with ibrutinib may provide insight into the mechanisms of resistance. We performed whole exome sequencing on sequential samples with matched germline controls from 61 patients with CLL during the first 12 months of ibrutinib monotherapy or ibrutinib in combination with rituximab. Additionally, RNA sequencing was done on a subset of 14 patients treated with ibrutinib monotherapy. The presence of clonal shifts was associated with an increased risk of disease progression, suggesting that resistant clones are more likely to emerge in CLL with greater evolutionary capacity.This cohort was later augmented with additional data (including data from 15 additional patients). In total, this second set of data contained whole exome sequencing (31 samples), RNA sequencing (6 samples) and reduced representation bisulfite sequencing (67 samples) for CLL samples and used them to identify expression subtypes of CLL. In an integrative analysis of genetic, transcriptomic, and epigenetic data, incorporating known and newly identified subtypes of CLL, we built new models to improve patient prognostication.

  Study phs001473

• Experimental PfSPZ Vaccine in Adults Without Malaria

  The study was performed to evaluate whole-blood transcriptomic profiles via RNA-seq before, during, and after immunization with the PfSPZ Vaccine in malaria-naïve, healthy adults enrolled in VRC 312 (NCT01441167). VRC 312 was the second study of the PfSPZ Vaccine and the first study to evaluate intravenous (IV) administration of this vaccine. The study was an open-label evaluation of the safety, tolerability, immunogenicity, and protective efficacy of the vaccine at successively higher administered by the IV route. The highest dosages were evaluated for protection against a malaria challenge after 4 to 6 vaccinations. The primary objectives of the study were related to the safety and tolerability of the vaccine at the 4 different dosage levels when administered IV; the secondary objectives were related to PfSPZ vaccine-mediated protection against Plasmodium falciparum (Pf) challenge at the 3 higher dosage levels, and the exploratory objectives were related to the immunogenicity of the PfSPZ Vaccine and defining an immune correlate of protection. To further determine potential molecular correlates of immunogenicity and/or protection, RNA-seq was performed on whole blood collected from subjects in all dose groups at time points before, during, and after immunization.

  Study phs002422

• Whole Exome and Transcriptome Sequencing in Sporadic ALS

  Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal and devastating neurodegenerative disorder that causes the progressive death of upper and lower motor neurons. Although many efforts have been done to elucidate molecular factors involved in the onset and progression of the disorder, the causes of ALS are yet unknown and undefined. Transcriptome studies, based mostly on microarrays, have revealed multiple perturbations of the motor neuron function, supporting the current idea that several cellular events contribute to the pathobiology of the disease, including mitochondrial dysfunction, enhanced apoptosis, glutamate-mediated excitotoxicity, free radical injury, protein misfolding, abnormal calcium metabolism and altered axonal transport. In the present study, we have deeply sequenced the whole transcriptome of ventral horns of the human lumbar spinal cord from matched control and ALS post-mortem donors. Whole exome sequencing from the same donors has also been performed to exclude known genetic variants associated to the familiar form of ALS. In addition, to characterize the ALS transcriptome we have sequenced the RNA fraction at low molecular weight in the same tissues and individuals. Genomic and transcriptomic reads have been generated using the Illumina HiSeq2000 sequencer.

  Study phs000747

• Characterizing TP53 and PPM1D Mutations as Resistance Drivers to Radiation Therapy in Diffuse Intrinsic Pontine Gliomas

  Pediatric high-grade gliomas (pHGGs), encompassing diffuse midline gliomas (DMGs) and hemispheric tumors, represent the most common cause of cancer-related deaths in children age 0-14 years. Over the last decade, several landmark papers have revealed recurrent single nucleotide variants (SNVs) in the core histones H3.3 and H3.1, co-occurring with alterations in the TP53 signaling pathway and receptor tyrosine kinases (RTKs). However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored. We performed a comprehensive analysis of whole genome sequencing (WGS) data on pediatric high-grade gliomas (pHGGs) from 179 children, including 61 hemispheric tumors and 118 diffuse midline gliomas, or DMGs, of which 61 are novel to this study. Among the DMGs, 84 (71%) were from pre-treatment biopsies including 33 obtained from the first multi-institutional North American clinical trial to incorporate diagnostic biopsies. This represents the largest cohort of pretreatment DMGs with whole genome sequencing to date. This large cohort of whole genome sequences provides an unparalleled opportunity to assess significantly recurrent structural variants in pHGG and their associations with driver SNVs and SCNAs. 

  Study phs002380