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• Postmortem Analysis of the Caudate Nucleus in Schizophrenia

  This postmortem study examines genomic signatures (gene, transcript, exon, and exon-exon junction) in the caudate nucleus of individuals with or without psychiatric illnesses. We characterized genetic and epigenetic changes across the lifespan of 443 donor subjects, including 245 individuals without psychiatric illness, 154 individuals with schizophrenia, and 44 individuals with bipolar disorder. The subjects are 210 from African and 233 from European ancestries. Combining expression quantitative trait loci (eQTL) analysis, Mendelian randomization with the latest schizophrenia genome-wide association study (GWAS), transcriptome-wide association study (TWAS) and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. There are 120 subjects in this study which are also present in the study phs000417.

  Study phs003495

• ScRNA-seq of human kidney immune cells of patients with ANCA-associated glomerulonephritis, Lupus Nephritis against a "healthy" nephrectomy control

  ANCA-associated glomerulonephritis (AGN) associates with a high risk of end-stage kidney disease. The role of kidney immune cells in local inflammation remains unclear. Here, we investigate kidney immune cell diversity and function. Kidney tissue from AGN patients (n=5) and a lupus nephritis (LN) patient (n=1) were aquired during a biopsy procedure for a clinical indication. Needle-core biopsies were obtained for histopathological examination, and an additional pass was performed to retrieve kidney tissue for scRNA-seq. Healthy kidney tissue (n=1) was obtained from a kidney that was surgically removed do tue due to a (non-invasive) papillary urothelial carcinoma. Immediately after collection, kidney tissue was processed into a single-cell suspension and sorted using a 4-color flow cytometry panel to isolate living, CD45+ immune cells. To aid in the multi-omic characterization, surface markers and T and B cell repertoires were sequenced in 2 samples (1 AGN patient and the nephrectomy control). These samples were incubated with an oligo-antibody TotalSeq-C cocktail containing 130 unique cell surface antigens.

  Study EGAS50000000159

• Transcriptomics sequencing analysis of pre-invasive lung adenocarcinoma in never-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000439

• Establishment of an iPSC Repository Derived from Healthy Volunteers

  Understanding the interaction between genetic variation and epigenetic variation remains a challenge due to the confounding role of environmental factors. We propose that human induced pluripotent stem cells (iPSCs) are an excellent model to study the relationship between genetic variation and epigenetic variation while controlling for consistent environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data of six iPSC lines and three iPS-derived cell types (NSC, Motor Neuron, Monocyte) from three healthy donors. We found that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in the differentiated cells. Additionally, cell-type is a stronger source of epigenetic variation than genetic variation, highlighting that humans are far more similar than they are different, regardless of genetic background. Further, we have elucidated a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell-types in which they may be acting.

  Study phs003649

• Whole exome sequencing of pre-invasive lung adenocarcinoma in non-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000438

• Anti-myeloperoxidase IgM B cells in anti-neutrophil cytoplasmic antibody-associated vasculitis

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a prototypic autoimmune disease, with a subset of AAV patients manifesting anti-myeloperoxidase (MPO) IgG. Patients with AAV respond positively to B cell-targeting and complement-targeting therapies, but disease flares are not uncommon. Here, by comparing samples from healthy individuals and MPO+ AVV patients, we show that B cell autoreactivity against MPO in the circulation of patients is dominated by CD27+IgM+ B cells whereas MPO-specific IgG+ cells are infrequent. Additionally, while naive anti-MPO-IgM B cells are present in both patients and controls and produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and serum anti-MPO IgM are features of patients. Our results thus hint that defective elimination of B cell reactivity to MPO in the human repertoire, the presence of activated IgM+ anti-MPO B cells in disease, and a dominant role for anti-MPO IgM in complement activation, may all contribute to MPO+ AAV etiology and thereby serve as potential target for therapy.

  Study EGAS50000000753

• Timing and trajectory of BCR-ABL1 driven chronic myeloid leukaemia

  Mutation of some genes provide fitness advantages that drive uncontrolled cell proliferation, leading to clinical manifestations of cancer. The discovery of the Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer and the hypothesis that this lesion provided an abnormal growth advantage to cells. However, little is known about the trajectory to CML, the rate of BCR::ABL1 driven clonal expansion, and how this impacts on disease presentation. Here, using whole-genome sequencing of 1013 single-cell-derived colonies from patients with CML, we reconstruct phylogenetic trees of haematopoiesis in 9 patients aged 22 to 81 years at diagnosis. The expected intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1 fusion transcripts, were noted in several patients. Apart from ASXL1 and RUNX1 mutations, additional somatic mutations in myeloid genes were generally present only in wild-type cells and did not contribute to the CML clone. Using phylogenetic analysis, we infer sustained explosive growth attributed to BCR::ABL1 fusion, with clonal expansions beginning 3-14 years (Cl 2-16 years) before diagnosis and annual growth rates exceeding 70,000% per year in some young patients with the most recent and rapid clonal expansions. Mutation rate was higher in BCR::ABL1-positive cells than in wild-type counterparts, together with markedly shorter telomere lengths, reflecting their excessive cell division history. Clonal expansion rates inferred from phylogenetic trees were in line with mutational signature patterns and telomere attrition, and inversely correlated with the time to diagnosis. Whole genome sequencing of advanced phase CML was characterised by genomic evolution within BCR::ABL1-positive cells. Our findings highlight the oncogenic potency of a single BCR::ABL1 fusion and its capacity to drive fast clonal outgrowth to cancer. These data contrast with the early-in-life, slow, and sequential clonal trajectories typical of most cancers, such as Philadelphia-negative myeloproliferative neoplasms, solid organ malignancies, and patterns of clonal expansion in healthy tissue ageing.

  Dataset EGAD00001015473

• CNA differences between RNA-based subtypes of PDAC

  Pancreatic ductal adenocarcinomas (PDAC) have a dismal prognosis with a 5-year survival of <5%. Chemoresistance and recurrences, seen in approximately 70% of PDAC patients, may partly be explained by intratumor heterogeneity (ITH) through which tumors may develop ‘escape routes’. In the Pancreas Multibiopsy (PM)-project we have obtained multiple fragments from pancreatic and other peri-ampullary carcinomas in order to reveal potential ITH and identify genetic aberrations that predict outcome after surgery and response to chemotherapy. CNA-profiles were used to complement the characterization of liabilities in PDAC that we identified previously using RNAseq in the form of epithelial, secretory, compound pancreatic, and mesenchymal subgroups that showed survival outcomes. Comparison of CNA-profiles between these transcriptomics-based subgroups (with 8, 3, 6, and 6 tumors respectively per group) showed differences, ranging from ‘quiet’(i.e. hardly any CNA) to ‘wild’(i.e. lots of CNA), but these were not statistically significant (Chi2 0.09). When differentiating between the classical and basal-like molecular subtypes of PDAC differences in CNA (high or low) were even less statistically significant (Chi2 0.292).

  Study EGAS50000001218

• Spatial transcriptomics analysis of triple negative breast cancers

  While triple negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigated TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We performed an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures led to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identified nine TNBC ecotypes, further validated in external datasets. Several ecotypes were associated with disease outcome and characterized by potentially actionable features. In this work, we provideThis is the largest TNBC series providing a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy. All the processed data needed to replicate the results from the publication (counts, images, clinical data, etc) are available on Zenodo: https://zenodo.org/records/14204217

  Study EGAS50000000475

• Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors

  Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE?neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non- CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.

  Study JGAS000131