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[Preprint]. 2024 Oct 11:2024.10.10.24315041.

doi: 10.1101/2024.10.10.24315041.

Genome-wide studies define new genetic mechanisms of IgA vasculitis

Lili Liu¹, Li Zhu², Sara Monteiro-Martins³, Aaron Griffin⁴, Lukas J Vlahos⁴, Masashi Fujita⁵, Cecilia Berrouet¹, Francesca Zanoni¹, Maddalena Marasa¹, Jun Y Zhang¹, Xu-Jie Zhou², Yasar Caliskan⁶, Oleh Akchurin⁷, Samhar Al-Akash⁸, Augustina Jankauskiene⁹, Monica Bodria¹⁰, Aftab Chishti¹¹, Ciro Esposito¹², Vittoria Esposito¹², Donna Claes¹³, Vladimir Tesar¹⁴, Thomas K Davis¹⁵, Dmitry Samsonov¹⁶, Dorota Kaminska¹⁷, Tomasz Hryszko¹⁸, Gianluigi Zaza¹⁹, Joseph T Flynn²⁰, Franca Iorember²¹, Francesca Lugani²², Dana Rizk²³, Bruce A Julian²³, Guillermo Hidalgo²⁴, Mahmoud Kallash²⁵, Luigi Biancone²⁶, Antonio Amoroso²⁶, Luisa Bono²⁷, Laila-Yasmin Mani²⁸, Bruno Vogt²⁸, Fangming Lin²⁹, Raji Sreedharan³⁰, Patricia Weng³¹, Daniel Ranch³², Nianzhou Xiao³³, Alejandro Quiroga³⁴, Raed Bou Matar³⁵, Michelle N Rheault³⁶, Scott Wenderfer³⁷, Dave Selewski³⁸, Sigrid Lundberg³⁹, Cynthia Silva⁴⁰, Sherene Mason⁴⁰, John D Mahan⁴¹, Tetyana L Vasylyeva⁴², Krzysztof Mucha⁴³, Bartosz Foroncewicz⁴³, Leszek Pączek⁴⁴, Michał Florczak⁴³, Małgorzata Olszewska⁴⁵, Agnieszka Gradzińska⁴⁶, Maria Szczepańska⁴⁷, Edyta Machura⁴⁷, Andrzej Badeński⁴⁷, Helena Krakowczyk⁴⁷, Przemysław Sikora⁴⁸, Norbert Kwella⁴⁹, Monika Miklaszewska⁵⁰, Dorota Drożdż⁵¹, Marcin Zaniew⁵², Krzysztof Pawlaczyk⁵³, Katarzyna SiniewiczLuzeńczyk⁵⁴, Andrew S Bomback⁵⁵, Gerald B Appel⁵⁵, Claudia Izzi⁵⁶, Francesco Scolari⁵⁶, Anna Materna-Kiryluk⁵⁷, Malgorzata Mizerska-Wasiak⁵⁸, Laureline Berthelot⁵⁹, Evangeline Pillebout⁶⁰, Renato C Monteiro⁶⁰, Jan Novak²³, Todd Jason Green²³, William E Smoyer⁴¹, M Colleen Hastings⁶¹, Robert J Wyatt^{62

63}, Raoul Nelson⁶⁴, Javier Martin⁶⁵, Miguel A González-Gay^{66

67}, Philip L De Jager⁵, Anna Köttgen^{3

68}, Andrea Califano^{4

69

70

71

72

73}, Ali G Gharavi¹, Hong Zhang², Krzysztof Kiryluk¹

Affiliations

¹ Department of Medicine, Division of Nephrology, Columbia University, College of Physicians & Surgeons, New York, NY, USA.
² Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
³ Institute of Genetic Epidemiology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Department of Systems Biology, Columbia University, New York, NY, USA.
⁵ Division of Neuroimmunology, Department of Neurology, Columbia University, New York, NY, USA.
⁶ Division of Nephrology, Saint Louis University, Saint Louis, MO, USA.
⁷ Weill Cornell Medical Center, New York, NY, USA.
⁸ Driscoll Children's Hospital, Corpus Christi, TX, USA.
⁹ Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.
¹⁰ MONICA BODRIA, MD, PHD, Primary Care Unit, Ausl Parma, south east district, Parma, Italy.
¹¹ Division of Pediatric Nephrology, University of Kentucky, Kentucky Children's Hospital, Lexington, KY, USA.
¹² Istituti Clinico Scientifici Maugeri IRCCS, University of Pavia, Pavia, Italy.
¹³ Cinncinnati Children's Hospital, Cincinnati, OH, USA.
¹⁴ Department of Nephrology, 1st School of Medicine, Charles University Prague, Czech Republic.
¹⁵ Washington University in Saint Louis, MO, USA.
¹⁶ Maria Fareri Children's Hospital (MCF), New York Medical College, New York, NY, USA.
¹⁷ Department of Non-Procedural Clinical Sciences, Faculty of Medicine, Wroclaw University of Science and Technology, Wroclaw, Poland.
¹⁸ 2nd Department of Nephrology, Hypertension and Internal Medicine, Medical University of Bialystok, Poland.
¹⁹ Renal, Dialysis and Transplant Unit, Department of Pharmacy, Health and Nutritional Sciences (DFSSN), University of Calabria.
²⁰ Department of Pediatrics, University of Washington; and Division of Nephrology, Seattle Children's Hospital.
²¹ Phoenix Children's Hospital, Phoenix, AZ, USA.
²² IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²³ University of Alabama at Birmingham, Birmingham, AL, USA.
²⁴ East Carolina University, Greenville, NC, USA.
²⁵ SUNY Buffalo, Buffalo, NY, USA.
²⁶ University of Turin, Italy.
²⁷ Nephrology and Dialysis, A.R.N.A.S. Civico and Benfratellio, Palermo, Italy.
²⁸ Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁹ Division of Pediatric Nephrology, Department of Medicine, Columbia University, New York, NY, USA.
³⁰ Medical College of Wisconsin, Madison, WI, USA.
³¹ University of California in Los Angeles, CA, USA.
³² UT Health San Antonio, San Antonio, TX, USA.
³³ Valley Children's Healthcare, Madera, CA, USA.
³⁴ Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
³⁵ Cleveland Clinic, Cleveland, OH, USA.
³⁶ University of Minnesota, Minneapolis, MN, USA.
³⁷ Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
³⁸ Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.
³⁹ Danderyd University Hospital, Karolinska Institute, Stockholm, Sweden.
⁴⁰ Connecticut Children's Medical Center, Hartford, CT, USA.
⁴¹ Nationwide Children's Hospital, Columbus, OH, USA.
⁴² Texas Tech University Health Sciences Center, Amarillo, TX, USA.
⁴³ Department of Transplantology, Immunology, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁴⁴ Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland.
⁴⁵ Department of Dermatology, Medical University of Warsaw, Warsaw, Poland.
⁴⁶ Department of Dermatology and Pediatric Dermatology, Centre of Postgraduate Medical Education, Warsaw, Poland.
⁴⁷ Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland.
⁴⁸ Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland.
⁴⁹ Department of Nephrology, Transplantology and Internal Diseases, University of Warmia and Mazury, Olsztyn, Poland.
⁵⁰ Department of Pediatric Nephrology and Hypertension, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁵¹ Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland.
⁵² Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland.
⁵³ Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland.
⁵⁴ Department of Paediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
⁵⁵ Columbia University Medical Center, New York, NY, US.
⁵⁶ Department of Medical and Surgical Specialties and Nephrology Unit, University of Brescia-ASST Spedali Civili, Brescia, Italy.
⁵⁷ Department of Genetics, Medical University of Poznan, Poznan, Poland.
⁵⁸ Department of Pediatrics and Nephrology, Medical University of Warsaw, 02-091 Warsaw, Poland.
⁵⁹ Nantes University, Inserm, CR2TI Center of Research on Translational Transplantation and Immunology, Nantes, France.
⁶⁰ Center for Research on Inflammation, Paris Cité University, INSERM and CNRS, Paris, France.
⁶¹ University of Tennessee Health Science Center, Memphis, TN, USA.
⁶² Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee.
⁶³ Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee.
⁶⁴ University of Utah, Salt Lake City, UT, USA.
⁶⁵ Institute of Parasitology and Biomedicine Lopez-Neyra, Spanish National Research Council (CSIC), Granada, Spain.
⁶⁶ Division of Rheumatology, IIS-Fundación Jiménez Díaz, Madrid, Spain.
⁶⁷ Medicine and Psychiatry Department, University of Cantabria, Santander, Spain.
⁶⁸ CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
⁶⁹ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
⁷⁰ Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷¹ Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷² Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷³ Chan Zuckerberg Biohub New York, New York, NY, USA.

PMID: 39417133
PMCID: PMC11482997
DOI: 10.1101/2024.10.10.24315041

Genome-wide studies define new genetic mechanisms of IgA vasculitis

Lili Liu et al. medRxiv. 2024.

[Preprint]. 2024 Oct 11:2024.10.10.24315041.

doi: 10.1101/2024.10.10.24315041.

Authors

Affiliations

¹ Department of Medicine, Division of Nephrology, Columbia University, College of Physicians & Surgeons, New York, NY, USA.
² Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
³ Institute of Genetic Epidemiology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Department of Systems Biology, Columbia University, New York, NY, USA.
⁵ Division of Neuroimmunology, Department of Neurology, Columbia University, New York, NY, USA.
⁶ Division of Nephrology, Saint Louis University, Saint Louis, MO, USA.
⁷ Weill Cornell Medical Center, New York, NY, USA.
⁸ Driscoll Children's Hospital, Corpus Christi, TX, USA.
⁹ Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.
¹⁰ MONICA BODRIA, MD, PHD, Primary Care Unit, Ausl Parma, south east district, Parma, Italy.
¹¹ Division of Pediatric Nephrology, University of Kentucky, Kentucky Children's Hospital, Lexington, KY, USA.
¹² Istituti Clinico Scientifici Maugeri IRCCS, University of Pavia, Pavia, Italy.
¹³ Cinncinnati Children's Hospital, Cincinnati, OH, USA.
¹⁴ Department of Nephrology, 1st School of Medicine, Charles University Prague, Czech Republic.
¹⁵ Washington University in Saint Louis, MO, USA.
¹⁶ Maria Fareri Children's Hospital (MCF), New York Medical College, New York, NY, USA.
¹⁷ Department of Non-Procedural Clinical Sciences, Faculty of Medicine, Wroclaw University of Science and Technology, Wroclaw, Poland.
¹⁸ 2nd Department of Nephrology, Hypertension and Internal Medicine, Medical University of Bialystok, Poland.
¹⁹ Renal, Dialysis and Transplant Unit, Department of Pharmacy, Health and Nutritional Sciences (DFSSN), University of Calabria.
²⁰ Department of Pediatrics, University of Washington; and Division of Nephrology, Seattle Children's Hospital.
²¹ Phoenix Children's Hospital, Phoenix, AZ, USA.
²² IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²³ University of Alabama at Birmingham, Birmingham, AL, USA.
²⁴ East Carolina University, Greenville, NC, USA.
²⁵ SUNY Buffalo, Buffalo, NY, USA.
²⁶ University of Turin, Italy.
²⁷ Nephrology and Dialysis, A.R.N.A.S. Civico and Benfratellio, Palermo, Italy.
²⁸ Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁹ Division of Pediatric Nephrology, Department of Medicine, Columbia University, New York, NY, USA.
³⁰ Medical College of Wisconsin, Madison, WI, USA.
³¹ University of California in Los Angeles, CA, USA.
³² UT Health San Antonio, San Antonio, TX, USA.
³³ Valley Children's Healthcare, Madera, CA, USA.
³⁴ Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
³⁵ Cleveland Clinic, Cleveland, OH, USA.
³⁶ University of Minnesota, Minneapolis, MN, USA.
³⁷ Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
³⁸ Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.
³⁹ Danderyd University Hospital, Karolinska Institute, Stockholm, Sweden.
⁴⁰ Connecticut Children's Medical Center, Hartford, CT, USA.
⁴¹ Nationwide Children's Hospital, Columbus, OH, USA.
⁴² Texas Tech University Health Sciences Center, Amarillo, TX, USA.
⁴³ Department of Transplantology, Immunology, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
⁴⁴ Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland.
⁴⁵ Department of Dermatology, Medical University of Warsaw, Warsaw, Poland.
⁴⁶ Department of Dermatology and Pediatric Dermatology, Centre of Postgraduate Medical Education, Warsaw, Poland.
⁴⁷ Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland.
⁴⁸ Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland.
⁴⁹ Department of Nephrology, Transplantology and Internal Diseases, University of Warmia and Mazury, Olsztyn, Poland.
⁵⁰ Department of Pediatric Nephrology and Hypertension, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁵¹ Department of Pediatric Nephrology and Hypertension, Jagiellonian University Medical College, Krakow, Poland.
⁵² Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland.
⁵³ Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland.
⁵⁴ Department of Paediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
⁵⁵ Columbia University Medical Center, New York, NY, US.
⁵⁶ Department of Medical and Surgical Specialties and Nephrology Unit, University of Brescia-ASST Spedali Civili, Brescia, Italy.
⁵⁷ Department of Genetics, Medical University of Poznan, Poznan, Poland.
⁵⁸ Department of Pediatrics and Nephrology, Medical University of Warsaw, 02-091 Warsaw, Poland.
⁵⁹ Nantes University, Inserm, CR2TI Center of Research on Translational Transplantation and Immunology, Nantes, France.
⁶⁰ Center for Research on Inflammation, Paris Cité University, INSERM and CNRS, Paris, France.
⁶¹ University of Tennessee Health Science Center, Memphis, TN, USA.
⁶² Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee.
⁶³ Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee.
⁶⁴ University of Utah, Salt Lake City, UT, USA.
⁶⁵ Institute of Parasitology and Biomedicine Lopez-Neyra, Spanish National Research Council (CSIC), Granada, Spain.
⁶⁶ Division of Rheumatology, IIS-Fundación Jiménez Díaz, Madrid, Spain.
⁶⁷ Medicine and Psychiatry Department, University of Cantabria, Santander, Spain.
⁶⁸ CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
⁶⁹ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
⁷⁰ Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷¹ Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷² Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷³ Chan Zuckerberg Biohub New York, New York, NY, USA.

PMID: 39417133
PMCID: PMC11482997
DOI: 10.1101/2024.10.10.24315041

Abstract

IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA-DRB1 (OR=1.55, P=1.1×10^-25) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10^-20) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10^-9) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR. Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR, INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS, and ANKRD55.

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Figures

**Figure 1.. GWAS meta-analysis for IgAV identified 3 genome-wide significant regions.**
**(A)** Manhattan plot with genome-wide significant loci highlighted in red; the dotted horizontal line indicates a genome-wide significance threshold (P=5×10–8). **(B)** Regional plots for the *INPP5D* locus (left), the *HLA* locus (middle), and the *FCAR* locus (right). The x-axis shows the physical position in kilobases (kb, hg19 coordinates) and includes known gene annotations; the left y-axis presents -log10 p-values for association statistics and the right y-axis shows the recombination rates; the dotted horizontal line indicates a genome-wide significant threshold of 5×10⁻⁸.

**Figure 2.. Effects of the *IL6R* locus.**
**(A)** Miami plot for PWAS and TWAS analyses. The red lines indicate the Bonferroni adjusted significance thresholds (5.6×10⁻⁵ for PWAS and 2.5×10⁻⁶ for TWAS). **(B)** Regional association plots for the *IL6R* locus. SNPs are plotted by position (hg19, 250kb window) versus −log10(P-values) from GWAS of IgAV (top), pQTL of plasma sIL6R levels (middle) and eQTL of *IL6R* expression in whole blood (bottom). The purple diamond highlights the most significant SNP for each association. SNPs are color-coded to reflect their LD with this SNP using LocusZoom with HapMap CEU reference. The missense variant *IL6R* p.Asp358Ala (rs2228145) is indicated in each plot. **(C)** The p.Asp358Ala substitution in relation to the cleavage site of the membrane bound IL6R. **(D)** Structure of the ADAM17 catalytic domain/IL-6R complex. The structure of ADAM17 (pale cyan ribbon render) was modeled with bound peptide 355-PVQDSSS-361 (yellow sticks in upper panel) or 355-PVQASSS-361 (pale orange sticks in lower panel) corresponding to a segment of the stalk region of IL-6R including the cleavage site (P355/V356). Residues of ADAM17 within 5 angstroms of D358 or A358 are shown as sticks. Polar interactions between residue 358 and ADAM17 are noted by dashed lines. The change D358A eliminates the interaction with N389 of ADAM17, potentially reducing the affinity of IL-6R for ADAM 17. Zinc and Sodium ions are shown as slate and purple spheres, respectively. Images generated with PyMOL (Molecular Graphics System, Version 2.0, Schrödinger, LCC).

**Figure 3.. Fine mapping of the *HLA* region in East Asian and European ancestry cohorts.**
**(A)** Regional plot for the East Asian cohort with bi-allelic and multi-allelic association statistics for all imputed variants and classical HLA alleles; the strongest association signal was for *HLA-DRB1* (upper panel); the results for *HLA-DQA1* and *HLA-DQB1* are highlighted for reference; after controlling for *HLA-DRB1* classical alleles (black arrow), there was no residual association across the entire 3-Mb region (lower panel). **(B)** Regional plot for the European cohorts with bi-allelic and multi-allelic association statistics for all imputed variants and classical HLA alleles; after controlling for *HLA-DRB1* classical alleles, there were no significant associations in the region (lower panel). The dotted horizontal line indicates the genome-wide significance threshold (α=5×10⁻⁸). **(C)** East Asian analysis of polymorphic amino acid positions within DRβ1 (blue), DQα1 (green) and DQβ1 (orange) using conditional-haplotype tests; the horizontal dash line indicates the genome-wide significance level. The most strongly associated polymorphic site was position 11 in DRβ1 (left panel); after controlling for this position, there was no residual association (right panel). **(D)** European analysis of polymorphic amino acid positions within DRβ1 (blue), DQα1 (green) and DQβ1 (orange); consistent with East Asian analysis, the DRβ1 amino acid position 11 (left panel) provided the strongest signal; no additional independent positions were found upon conditioning on this position (right panel). **(E)** Structure of the DRα1-DRβ1 complex. The protective variant (P11, left) and risk variants (V11, middle and L11, right) are shown in surface model viewed into the peptide binding groove. Models are colored in a background of light blue shade, with individual peptide amino acid binding pockets shaded according to the provided color key.

**Figure 4.. Functional annotations of the *FCAR* locus**
(a) The heatmap of FUN-LDA functional scores for the lead SNP (rs77149320, red) and its high LD proxies (r²>0.8, only SNPs and cell types with positive scores are depicted). The 7 SNPs in LD (names in blue) intersected an ABC model-predicted intronic enhancer of *FCAR*. This regulatory region was further confirmed by an ATAC-seq peak in monocytes before and after LPS treatment. The prioritized SNPs were analyzed against transcription factor binding motifs predicted by JASPAR, and two risk alleles (rs4806602-G and rs73065472-T in perfect LD and two base pairs apart) were found to disrupt the PRDM1 binding motif; (b) Co-localization of the *FCAR* locus between GWAS for IgAV and blood eQTL for *FCAR* in IgAV (top two panels), and GWAS for IgAN and blood sQTL for *FCAR* in IgAV (bottom two panels). The eQTL effect shown in the right upper panel (x-axis: genotypes, y-axis: normalized expression of *FCAR*). The sQTL effect shown in the right bottom panel (x-axis: genotypes, y-axis: normalized exclusion rate of chr19:54885525–54885805 region based on hg38 annotations, the splice model depicted above).

**Figure 5.. Master regulators of IgA vasculitis modulated by the GWAS candidate genes.**
(a) the UMAP plot for the reference single cell RNA-seq data from 163 healthy individuals. The blood cells were clustered and annotated into 15 different immune cell types highlighted in different colors; (b) Deconvolution and differential gene expression analysis based on blood bulk RNA-seq data from 255 IgAV cases and 38 health controls. The upper panel shows the distribution of different cell type fractions across all 293 individuals. The volcano plot (lower panel: x-axis denotes the log2 Fold Change and the y-axis indicates the adjusted P values) with differentially expressed genes in red (P_adjusted<0.05 and log2 Fold Change>0.2) after adjusting for cell type fractions; (c) The myeloid regulons reconstructed transcriptome-wide based on the myeloid lineage cells (circled in red above) using ARACNe3 software (a subset of only 3 regulons shown to illustrate this step). (d) Differential activity analysis based on the myeloid regulons and cell fraction-adjusted differential gene expression signature in IgAV cases compared to controls. The x-axis indicates the proportional enrichment score (effect size for gene set enrichment that was normalized by set’s size, parameterization, and gene expression signature). The y-axis shows the normalized score compared to the expectation under the null hypothesis. The red and blue colors indicate the regulators with higher and lower activity, respectively, in IgAV cases compared to healthy controls. (e) Regulators co-modulated by the GWAS candidate genes: 1,072 regulators co-modulated by *FCAR* and *INPP5D* with mostly opposed effects on their biological activities (upper panel) and 1,009 regulators co-modulated by *FCAR* and *IL6R* with direction consistent effects on their biological activities (lower panel). The targets of the top master regulators co-modulated by all 3 genes were enriched in multiple immune related pathways based on FDR< 0.05 (depicted as enrichment map with a node size proportional to the statistical significance of enrichment and edge thickness proportional to gene set overlaps).

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This is a preprint.

Genome-wide studies define new genetic mechanisms of IgA vasculitis

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Genome-wide studies define new genetic mechanisms of IgA vasculitis

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