Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

Objective Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p<1.0×10–5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10–8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10–9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

[1]  Y. Kamatani,et al.  Genome-wide association study of colorectal polyps identified highly overlapping polygenic architecture with colorectal cancer , 2021, Journal of Human Genetics.

[2]  M. Ritchie,et al.  From GWAS to Gene: Transcriptome-Wide Association Studies and Other Methods to Functionally Understand GWAS Discoveries , 2021, Frontiers in Genetics.

[3]  Stephanie A. Bien,et al.  Transcriptome-Wide Association Study of Blood Cell Traits in African Ancestry and Hispanic/Latino Populations , 2021, Genes.

[4]  F. Pedersen,et al.  A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology , 2021, EBioMedicine.

[5]  C. Wallace A more accurate method for colocalisation analysis allowing for multiple causal variants , 2021, bioRxiv.

[6]  Y. Lau,et al.  Genome-wide association study on Northern Chinese identifies KLF2, DOT1L and STAB2 associated with systemic lupus erythematosus. , 2021, Rheumatology.

[7]  M. Weirauch,et al.  Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus , 2020, Annals of the Rheumatic Diseases.

[8]  H. Wheeler,et al.  Population-Matched Transcriptome Prediction Increases TWAS Discovery and Replication Rate , 2020, iScience.

[9]  Adam C. Labonte,et al.  Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries. , 2020, American journal of human genetics.

[10]  Jacob C. Ulirsch,et al.  Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases , 2020, Nature Genetics.

[11]  S. Grant,et al.  Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells , 2020, Nature Communications.

[12]  G. Trynka,et al.  From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases , 2020, Frontiers in Genetics.

[13]  Y. Muller,et al.  The CD83 Molecule – An Important Immune Checkpoint , 2020, Frontiers in Immunology.

[14]  Adam C. Labonte,et al.  The pathogenesis of systemic lupus erythematosus: Harnessing big data to understand the molecular basis of lupus. , 2019, Journal of autoimmunity.

[15]  Arjun Bhattacharya,et al.  A framework for transcriptome-wide association studies in breast cancer in diverse study populations , 2019, Genome Biology.

[16]  K. Jepsen,et al.  TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases , 2019, Cell reports.

[17]  Michael Wainberg,et al.  Opportunities and challenges for transcriptome-wide association studies , 2019, Nature Genetics.

[18]  A. Gusev,et al.  Probabilistic fine-mapping of transcriptome-wide association studies , 2017, Nature Genetics.

[19]  Y. Kamatani,et al.  PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes , 2019, Annals of the rheumatic diseases.

[20]  R. Sun,et al.  The Ca2+ sensor STIM1 regulates type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum , 2018, Nature Immunology.

[21]  Alexander Gusev,et al.  Large-scale transcriptome-wide association study identifies new prostate cancer risk regions , 2018, Nature Communications.

[22]  B. Cravatt,et al.  PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing , 2018, Nature Immunology.

[23]  Y. Kamatani,et al.  Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis , 2017, Nature Genetics.

[24]  Doron Lancet,et al.  GeneHancer: genome-wide integration of enhancers and target genes in GeneCards , 2017, Database J. Biol. Databases Curation.

[25]  Y. Gwack,et al.  Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes. , 2017, Advances in experimental medicine and biology.

[26]  Kathleen E. Sullivan,et al.  New insights into the immunopathogenesis of systemic lupus erythematosus , 2016, Nature Reviews Rheumatology.

[27]  A. Clarke,et al.  The global burden of SLE: prevalence, health disparities and socioeconomic impact , 2016, Nature Reviews Rheumatology.

[28]  Alexander Gusev,et al.  Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights , 2016, Nature Genetics.

[29]  Xuejun Zhang,et al.  Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus , 2016, G3: Genes, Genomes, Genetics.

[30]  Y. Baba,et al.  Role of Calcium Signaling in B Cell Activation and Biology. , 2015, Current topics in microbiology and immunology.

[31]  T. Lehtimäki,et al.  Integrative approaches for large-scale transcriptome-wide association studies , 2015, Nature Genetics.

[32]  S. Feske,et al.  Diseases caused by mutations in ORAI1 and STIM1 , 2015, Annals of the New York Academy of Sciences.

[33]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[34]  G. Kempermann Faculty Opinions recommendation of Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. , 2015 .

[35]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[36]  Joris M. Mooij,et al.  MAGMA: Generalized Gene-Set Analysis of GWAS Data , 2015, PLoS Comput. Biol..

[37]  J. Hirschhorn,et al.  Biological interpretation of genome-wide association studies using predicted gene functions , 2015, Nature Communications.

[38]  Y. Okada,et al.  The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations , 2014, Nature Communications.

[39]  P. Randazzo,et al.  The Arf6 GTPase-activating Proteins ARAP2 and ACAP1 Define Distinct Endosomal Compartments That Regulate Integrin α5β1 Traffic* , 2014, The Journal of Biological Chemistry.

[40]  A. Steinkasserer,et al.  Soluble human CD83 ameliorates lupus in NZB/W F1 mice. , 2013, Immunobiology.

[41]  Howard Y. Chang,et al.  Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position , 2013, Nature Methods.

[42]  Judy H. Cho,et al.  Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3 , 2013, Genes and Immunity.

[43]  S. Feske,et al.  Ion channels , 2013, Thorax.

[44]  T. Vyse,et al.  The genetics of lupus: a functional perspective , 2012, Arthritis Research & Therapy.

[45]  Y. Okada,et al.  A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese , 2012, PLoS genetics.

[46]  A. Syvänen,et al.  Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus , 2011, PLoS genetics.

[47]  M. Hallek,et al.  Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. , 2010, Neoplasia.

[48]  R. Panettieri,et al.  Glucocorticoid receptor interacting protein-1 restores glucocorticoid responsiveness in steroid-resistant airway structural cells. , 2010, American journal of respiratory cell and molecular biology.

[49]  Gerald McGwin,et al.  A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus , 2009, Nature Genetics.

[50]  Ying Wang,et al.  Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus , 2009, Nature Genetics.

[51]  L. Pasquier,et al.  Orphanet Journal of Rare Diseases , 2006 .