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• Autism Genome Project (AGP) Consortium - Whole Genome Association Study of over 1,500 Parent-Offspring Trios - Stage I and II

  Autism spectrum disorders (ASDs) are highly heritable (~90%), yet the underlying genetic determinants are largely unknown. To understand the genetic and phenotypic heterogeneity in ASDs, we analyzed 2,611 strictly defined ASD families with over 1,000,000 single nucleotide polymorphisms (SNPs), and applied multiple analytical strategies to examine these families for SNPs and Copy Number Variation (CNVs) affecting risk for ASDs. Secondary analyses examined associations in more homogenous subgroups. Furthermore, the use of large control datasets permitted contrasting case and control samples and addressed the potential increased burden of rare CNVs in ASD. Our data have allowed us to discern key features of the ASD genomic architecture, find new susceptibility loci, and chart a course for future studies in ASDs.

  Study phs000267

• The Iberian Roma genetic variant server

  The Roma are the most numerous ethnic minority in Europe. The Iberian Roma arrived in the Iberian Peninsula five centuries ago and still today, they keep a strong group identity. Demographic and cultural reasons lie behind a high rate of Mendelian disease often related to founder variants. We have analysed exome data from 119 Iberian Roma individuals collected from 2018 to 2020. A database of variant frequency has been implemented (IRPVS) and made available online. We have analysed the carrier rate of founder private alleles as well as pathogenic variants present in the general population. Significant enrichment in structural variants involving gene clusters related to keratinization and epidermal growth suggest that evolutive mechanisms have developed towards climate and environmental adaptation. IRPVS can be accessed at http://irpvs.clinbioinfosspa.es/

  Study EGAS00001006758

• Molecular Determinants of Tumor Behavior in Early Lung Adenocarcinoma

  Lung adenocarcinoma is the leading cause of cancer death worldwide and a heterogeneous disease with poor survival in the advanced stage. Given that the frequency of early diagnosis is increasing, the investigation of the molecular determinants of disease progression is paramount. Prediction of whether the tumor is indolent or aggressive has been the subject of recent investigations. Yet, the molecular underpinnings explaining the difference in tumor behavior remains largely unknown and is directly relevant to the efficacy and cost-effectiveness of lung cancer screening, including the risks of over-diagnosis and overtreatment. To gain insights into the molecular pathogenesis and the underlying molecular determinants of clinical behavior of early adenocarcinoma, we investigated genetic alterations in 102 surgically resected early adenocarcinomas. We hypothesized that the behavior of early adenocarcinoma can be predicted based on genomic underpinnings. To identify the type of genomic alterations associated with resected indolent and aggressive early lung ADC, the DNA samples from 21 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA) and 54 fully invasive adenocarcinoma were collected and subjected to a deep next generation sequencing, targeting a custom 347 cancer gene panel. Our study provides new insights into cancer genomic evolution, helps to elucidate the interplay of somatic mutation and the adaptation of clones, and brings new insights into the key distinction between indolent and aggressive tumor behavior.

  Study phs001811

• Genomic Evolution of Low- and High-Grade Glioma

  Malignant transformation (MT) of IDH-mutant low-grade glioma (LGG) to aggressive high-grade tumors is an event of major clinical significance, eventually leading to death in the majority of LGG patients. While patients with primary glioblastoma (GBM) have benefited from increased overall survival due to treatment with the alkylating chemotherapy temozolomide (TMZ), the benefit of TMZ for patients with diffuse low-grade gliomas (LGG) remains unknown. To further explore the relationships among TMZ treatment, hypermutation and malignant progression, we studied tumor evolution in an expanded cohort of untreated and TMZ-treated patients by exome-sequencing of paired IDH1/2-mutant LGGs and their post-TMZ recurrences. Together, these findings further our understanding of the molecular features and clinical behavior of hypermutated clones. The heterogeneity present in individual tumors, i.e. intratumoral heterogeneity (ITH), is thought to be a major reason why targeted treatments eventually fail. However, we know little about ITH in most human tumors because studies typically analyze one biopsy per tumor without knowledge of where in the tumor the sample was taken. Understanding how malignant and non-malignant cellular populations are distributed in 3D tumor space is foundational knowledge for resolving how human tumors grow, with translational implications for identifying representative biopsy specimens and predicting the impact of targeted therapy. Diffuse gliomas are incurable brain tumors with variably aggressive molecular subtypes. To determine the extent of ITH and its 3D organization in diffuse glioma, we prospectively collected a median of 10 spatially mapped samples from newly diagnosed and recurrent patient tumors, including aggressive canonical IDH1/IDH2 wild-type (IDH-wtc) glioblastoma, slower-growing IDH1/IDH2 mutant (IDHmut) glioma and a noncanonical IDH-wt glioblastoma (IDH-wtnc) lacking the TERT promoter mutation typical of canonical Glioblastoma.

  Study phs002034

• PD-L1 blockade immunotherapy rewires cancer-induced emergency myelopoiesis

  Introduction Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Methods In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow HSPCs. We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality. Results Herein, we reveal that aPD-L1 in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice. Discussion: Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.

  Study EGAS00001007873

• Adipose Tissue Omics In Obesity

  This project used a multi-omics approach to study the adipose tissue transcriptome in humans with and without obesity. Our human cohort included males and females between the ages of 18-80 who underwent elective abdominal surgery at the University of Michigan and the Ann Arbor Veterans Affairs Healthcare System.Patients with advanced cancer or immuncompromised status were excluded. Visceral adipose tissue (VAT/omental) and subcutaneous adipose tissue (SAT/abdominal wall) were collected from subjects with obesity (BMI>=35) at the beginning of elective surgical procedures, placed on ice, and transported back to the laboratory for immediate processing. For adipose tissue stromal cells (ASC) isolation, adipose tissue was digested with Type II collagenase (2 mg/mL in PBS/2% BSA) at 37oC, 60min, centrifuged at 250 rcf, and the stromal-vascular cell pellet was retrieved, plated overnight, and the adherent cells passaged three times to enrich for ASC, which were then frozen in DMEM/F12, 15% fetal calf serum, and 10% DMSO in liquid nitrogen until use. Single nuclear sequencing was performed on preparations from intact adipose tissue. Bulk RNA sequencing and single cell sequencing were performed on ASC isolated from intact adipose tissue and cultured in 2D and 3D culture systems. We currently apply bulk, single cell, and single nuclear sequencing analyses to these tissues. One component of this project studies single nuclear sequencing in nuclei isolated from intact adipose tissues from human subjects with obesity, focusing on depot comparisons (VAT vs. SAT). This cohort also permits comparisons of adipose tissue transcriptomes between male and female subjects, controlling for age and BMI. Primary findings to date include identification of multiple ASC, adipocyte, and endothelial cell (EC) subpopulations, T-cell, and macrophage (MAC) populations that are in concordance with and expand upon other published datasets. Of two dominant ASC subpopulations, one (inflammatory-mesothelial, IM- ASC) is present in VAT, but absent in SAT, while the other (fibroadipogenic, FA-ASC) is present in both VAT and SAT. We identified multiple EC subtypes with features of lymphatic, venous, and arterial EC, and a PRDM16 expressing population with features of an EC progenitor. Immune cell populations match recent experimental validation of lipid-activated macrophage (LAM) phenotypes, TIM4 macrophages, and a prominent population of MRC1/CD206+ resident AT macrophages with expression signatures related to glucocorticoid activation. These data support depot-specific differences in ASC subpopulations and previously unrecognized EC heterogeneity within human AT, with the potential to shed light on functional differences in AT depot and disease state. Planned future studies include ATAC-Seq and other omics analyses. Another component of this project studies transcriptional responses of ASC in vitro to various stimuli, including different matrix environments. Current data includes bulk RNA Sequencing of human ASC from VAT and SAT differentiated into mature adipocytes in hydrogels of differing stiffness (3%, 5%, 10%) to define transcriptional responses to matrix environments of different stiffness. Primary findings to date include enrichment of adipogenesis and lipid and oxidative metabolic gene pathways in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways have been enriched in 3% hydrogels. These data demonstrate that intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. Planned future studies include expansion of intact tissues from our cohort studied with single nuclear sequencing, as well as further study of ASC responses in vitro to different biologic stimuli, including different matrix environments.

  Study phs003390

• Deep single-cell RNA sequencing data for 11138 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive CRC patients. The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any scientific research program complying with the laws and bioethic regulation policies of China will be approved.

  T cells are central players in cancer immunotherapy1, yet some of their fundamental properties such as development and migration within tumours remain elusive. The enormous T cell receptor (TCR) repertoire, required for recognising foreign and self-antigens2,3, could serve as lineage tags to track these T cells in tumours4. Here, we obtained transcriptomes of 11,138 single T cells from 12 colorectal cancer (CRC) patients and developed STARTRAC (Single T-cell Analysis by Rna-seq and Tcr TRACking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While both CD8+ effector and “exhausted” T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable response rates to immune-checkpoint blockade. Furthermore, we found IGFLR1 to be highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provides a powerful avenue to comprehensively dissect the T cell properties in CRC, which could shed new insights into the dynamic relationships of T cells in other cancers

  Study EGAS00001002791

• Analyzing Somatic Mutagenesis in Systemic Sclerosis

  The study was undertaken with the aim of estimating differences in the mutational burden in lung tissues from healthy vs systemic sclerosis (SSc) patients. SSc is an auto-immune disease, with patients often developing cancer. However, the etiology of this phenomenon is poorly understood. As such we sought to uncover potential molecular mechanisms prevalent within SSc tissues that might be potentiating cancer. Samples were randomly collected from individuals from two broad ethnic groups, European (EA) and African American (AA). In total, samples were obtained from 7 individuals belonging to the EA group and 4 individuals from the AA group. For this study, ethnicity was not included as a confounding variable, given that the data set has roughly comparable number of individuals from both ethnicities for the healthy and SSc cohorts. Study participants ranged in age from 37-63 years old. Median age (52 years old) of healthy individuals was comparable to the SSc cohort (~48 years old). Participants were self-described as current/former smokers or non-smokers. Lung tissues were obtained under a protocol approved by the University of Pittsburgh Institutional Review Board. Written informed consent statements were provided to the University of Pittsburgh IRB by the study participants/patients. Sample sizes were determined by the ability of bulk lung fibroblast tissues to stably propagate in culture until single cell clones could be obtained. Samples for which sufficient cell density could not be achieved for downstream high-depth sequencing analysis were excluded from the study and are not reported. Five or greater than 5 samples are collected from each cohort including healthy and SSc patients. Subjects were allocated to two basic cohorts based on diagnosis at the time of explant. Participants with no reported lung anomalies were allocated to the "healthy" cohort, whereas individuals with reported lung abnormalities, primarily SSc with pulmonary fibrosis and/or hypertension were allocated to the "SSc" cohort. All tissue samples were cultured, propagated and processed in identical fashion without requiring individual-specific protocols. Additionally, equivalent amounts of DNA were used for preparing sequencing libraries from both cohorts, and all samples were sequenced using Illumina whole genome sequencing (WGS) and analyzed using identical computational pipelines. Our study primarily discovered that there is a significantly higher burden of somatic mutations in SSc samples, compared to healthy samples. We observed an overall increase in a range of mutations in genomes of SSc patients, including single base substitutions, indels, structural variants and copy number alterations. Additionally, we uncovered a novel mutation signature associated with SSc samples, hinting at the activity of POLH in these samples, and highlighting the potential nexus between inflammation, DNA damage, and cancer.

  Study phs003700

• RNAseq in blood CD34+ cells

  The aim of the project was to perform expression quantitative trait locus (eQTL) analysis in blood CD34+ cells from random blood donors.

  Study EGAS00001005655

• Genetic Causes of Congenital Anosmia

  The Genetic Causes of Congenital Anosmia study was designed to provide a list of candidate genes that are potentially causal for isolated congenital anosmia (ICA), a rare inherited disorder where individuals lack a sense of smell from birth in the absence of a known genetic syndrome (i.e. Kallman's syndrome). This study includes 193 participants from 18-87 years of age, divided into two cohorts: family and non-family. Genetic data from the family cohort was analyzed in a case-control family design to generate a list of 162 candidate genes for ICA. A targeted search for variants in this list of genes was then conducted in the non-family cohort to create a prioritized list of genes for further study. Ten unrelated families were recruited for the family cohort for a total of 52 participants, 25 of which had anosmia. The non-family cohort consisted of 141 anosmic individuals. 3 additional normosmic participants from incomplete families were collected, one of whom has a participating family member in the non-family cohort, and so has data provided here. Data collection was conducted remotely, resulting in 146 participants recruited from the United States, and 48 recruited internationally from ten different countries. Participants were interviewed for their anosmia status and to confirm that they had no known genetic syndromes. Participants also completed the University of Pennsylvania Brief Smell Identification Test (BSIT; Doty et al., 1984) to confirm their anosmic/normosmic status and provided a saliva sample for whole exome sequencing (WES). Participants who had family members with anosmia provided pedigree information via interview. Data submitted to dbGap include whole exome sequences from 194 individuals (163 anosmic) conducted with Illumina HiSeq2500 and Illumina NovaSeq next generation sequencing technologies. Family pedigree information for the 10 participating families and all participants in the non-family cohort who have non-participating anosmic family members was also included. Our goal was to provide a resource for further research into the genetics of isolated congenital anosmia and to aide in the understanding of this disorder, as well as human olfaction, in general. The WES data provided could be further analyzed for polygenic interactions, additional non-targeted analysis on the non-family cohort, or combined into databases of other anosmic populations for further gene targeting or selection.

  Study phs003328