Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci1-8. Nevertheless, these loci only partially explain SLE heritability and provide limited biological insight. We report the largest study of SLE in East Asians (13,377 cases and 194,993 controls), identifying 233 association signals within 113 (46 novel) genetic loci. We detect six new lead missense variants and prioritize ten most likely putative causal variants, one of which we demonstrate exhibits allele-specific regulatory effect on ACAP1 in vitro. We suggest 677 effector genes with potential for drug repurposing, and provide evidence that two distinct association signals at a single locus act on different genes (NCF2 and SMG7). We demonstrate that SLE-risk variants overlap with cell-specific active regulatory elements, notably EBNA2-mediated super-enhancers in Epstein-Barr Virus-transformed B cells, and implicate the role for non-immune cells in SLE biology. These findings shed light on genetic and biological understandings of SLE.

[1]  M. Kanai,et al.  Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases , 2020, Nature Genetics.

[2]  Y. Kamatani,et al.  Predicting cell-type-specific non-coding RNA transcription from genome sequence , 2020, bioRxiv.

[3]  P. Gaffney,et al.  Role of Systemic Lupus Erythematosus Risk Variants With Opposing Functional Effects as a Driver of Hypomorphic Expression of TNIP1 and Other Genes Within a Three‐Dimensional Chromatin Network , 2020, Arthritis & Rheumatology.

[4]  P. Gaffney,et al.  Role of Systemic Lupus Erythematosus Risk Variants With Opposing Functional Effects as a Driver of Hypomorphic Expression of TNIP1 and Other Genes Within a Three‐Dimensional Chromatin Network , 2019, Arthritis & rheumatology.

[5]  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.

[6]  Y. Kamatani,et al.  GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation , 2019, Nature Communications.

[7]  Anshul Kundaje,et al.  The ENCODE Blacklist: Identification of Problematic Regions of the Genome , 2019, Scientific Reports.

[8]  M. Sannigrahi,et al.  The strong propensity of Cadherin‐23 for aggregation inhibits cell migration , 2019, Molecular oncology.

[9]  Scott M. Williams,et al.  The Missing Diversity in Human Genetic Studies , 2019, Cell.

[10]  Y. J. Kim,et al.  The Korea Biobank Array: Design and Identification of Coding Variants Associated with Blood Biochemical Traits , 2019, Scientific Reports.

[11]  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.

[12]  Helen E. Parkinson,et al.  The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 , 2018, Nucleic Acids Res..

[13]  Y. Okada,et al.  IMPACT: Genomic Annotation of Cell-State-Specific Regulatory Elements Inferred from the Epigenome of Bound Transcription Factors , 2019, American journal of human genetics.

[14]  P. Donnelly,et al.  The UK Biobank resource with deep phenotyping and genomic data , 2018, Nature.

[15]  Christopher D. Brown,et al.  QuASAR‐MPRA: accurate allele‐specific analysis for massively parallel reporter assays , 2018, Bioinform..

[16]  Chang-Keun Lee,et al.  Predicting eventual development of lupus nephritis at the time of diagnosis of systemic lupus erythematosus. , 2018, Seminars in arthritis and rheumatism.

[17]  Daniel E. Miller,et al.  Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity , 2018, Nature Genetics.

[18]  Liangdan Sun,et al.  Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population , 2017, Annals of the rheumatic diseases.

[19]  Erdogan Taskesen,et al.  Functional mapping and annotation of genetic associations with FUMA , 2017, Nature Communications.

[20]  Jay W. Shin,et al.  FANTOM5 CAGE profiles of human and mouse samples , 2017, Scientific Data.

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

[22]  Andrew P Morris,et al.  Guidance for the utility of linear models in meta-analysis of genetic association studies of binary phenotypes , 2016, European Journal of Human Genetics.

[23]  D. Isenberg,et al.  A study of the influence of ethnicity on serology and clinical features in lupus , 2015, Lupus.

[24]  Anthony D. Schmitt,et al.  A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome. , 2016, Cell reports.

[25]  Alan M. Kwong,et al.  Next-generation genotype imputation service and methods , 2016, Nature Genetics.

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

[27]  Lu,et al.  Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus , 2016, Nature Genetics.

[28]  Shane A. McCarthy,et al.  Reference-based phasing using the Haplotype Reference Consortium panel , 2016, Nature Genetics.

[29]  J. McPherson,et al.  Coming of age: ten years of next-generation sequencing technologies , 2016, Nature Reviews Genetics.

[30]  T. Hirano,et al.  LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation , 2016, Scientific Reports.

[31]  R. Cantor,et al.  Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production , 2016, Annals of the rheumatic diseases.

[32]  Y. J. Kim,et al.  High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry , 2016, Nature Genetics.

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

[34]  H. Tozkır,et al.  BLK pathway-associated rs13277113 GA genotype is more frequent in SLE patients and associated with low gene expression and increased flares , 2016, Clinical Rheumatology.

[35]  J. Rioux,et al.  Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus , 2015, Nature Genetics.

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

[37]  Matti Pirinen,et al.  FINEMAP: efficient variable selection using summary data from genome-wide association studies , 2015, bioRxiv.

[38]  Yakir A Reshef,et al.  Partitioning heritability by functional annotation using genome-wide association summary statistics , 2015, Nature Genetics.

[39]  Ji Zhang,et al.  GREGOR: evaluating global enrichment of trait-associated variants in epigenomic features using a systematic, data-driven approach , 2015, Bioinform..

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

[41]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

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

[43]  Don L. Armstrong,et al.  Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 Mutation Affects the Structure of NADPH Oxidase Complex* , 2015, The Journal of Biological Chemistry.

[44]  E. Kieff,et al.  Epstein-Barr virus oncoprotein super-enhancers control B cell growth. , 2015, Cell host & microbe.

[45]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

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

[47]  P. Gaffney,et al.  Lupus risk variants in the PXK locus alter B-cell receptor internalization , 2015, Front. Genet..

[48]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[49]  Jiangshan J. Shen,et al.  Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus. , 2015, Human molecular genetics.

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

[51]  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.

[52]  Andrew M. Rupert,et al.  Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease , 2014, Nature Genetics.

[53]  N. ClarkDaniel,et al.  Molecular effects of autoimmune-risk promoter polymorphisms on expression, exon choice, and translational efficiency of interferon regulatory factor 5. , 2014 .

[54]  Ross M. Fraser,et al.  A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness , 2014, PLoS genetics.

[55]  T. Meehan,et al.  An atlas of active enhancers across human cell types and tissues , 2014, Nature.

[56]  Cesare Furlanello,et al.  A promoter-level mammalian expression atlas , 2015 .

[57]  L. Looger,et al.  Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. , 2014, Human molecular genetics.

[58]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[59]  Lissenya B. Argueta,et al.  Molecular effects of autoimmune-risk promoter polymorphisms on expression, exon choice, and translational efficiency of interferon regulatory factor 5. , 2014, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[60]  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.

[61]  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.

[62]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[63]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

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

[65]  P. Visscher,et al.  Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits , 2012, Nature Genetics.

[66]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[67]  Manolis Kellis,et al.  ChromHMM: automating chromatin-state discovery and characterization , 2012, Nature Methods.

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

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

[70]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[71]  J. Marchini,et al.  Genotype imputation for genome-wide association studies , 2010, Nature Reviews Genetics.

[72]  P. Sham,et al.  Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus , 2010, PLoS genetics.

[73]  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.

[74]  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.

[75]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[76]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[77]  Nancy F. Hansen,et al.  Accurate Whole Human Genome Sequencing using Reversible Terminator Chemistry , 2008, Nature.

[78]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[79]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[80]  J. Satia,et al.  Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden , 2006, Lupus.

[81]  S. Kaneko,et al.  Inhibition of Fas/Fas ligand-mediated apoptotic cell death of lymphocytes in vitro by circulating anti-Fas ligand autoantibodies in patients with systemic lupus erythematosus. , 1998, Arthritis and rheumatism.

[82]  M. Hochberg,et al.  Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. , 1997, Arthritis and rheumatism.