3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility.

Autor: Trang KB; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Sharma P; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Cook L; Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.; Department of Critical Care, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia.; Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC, Canada., Mount Z; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Thomas RM; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Kulkarni NN; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Pahl MC; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Pippin JA; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Su C; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Kaestner KH; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., O'Brien JM; Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.; Penn Medicine Center for Ophthalmic Genetics in Complex Disease., Wagley Y; Department of Orthopedic Surgery University of Michigan Medical School Ann Arbor, MI, USA., Hankenson KD; Department of Orthopedic Surgery University of Michigan Medical School Ann Arbor, MI, USA., Jermusyk A; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA., Hoskins JW; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA., Amundadottir LT; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA., Xu M; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA., Brown KM; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA., Anderson SA; Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Yang W; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Titchenell PM; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Seale P; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Zemel BS; Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Chesi A; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Romberg N; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Levings MK; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.; BC Children's Hospital Research Institute, Vancouver, BC, Canada.; School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada., Grant SFA; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Division Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Wells AD; Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 12. Date of Electronic Publication: 2024 Aug 12.
DOI: 10.1101/2024.08.12.24311676
Abstrakt: A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of gene cis -regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by these cis -regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of gene cis -regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.
Databáze: MEDLINE