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Prior studies had insufficient power to detect common variants because of small cohorts. By meta-analyzing two existing GWAS, the study discovers four novel common-variant signals and enriches SIgAD variants in genes tied to Mendelian immune disorders. It also finds shared architecture with serum IgA and immune-mediated diseases. Using pleiotropy via conditional false discovery rate, SIgAD results are conditioned on asthma and rheumatoid arthritis GWAS and on serum IgA meta-analysis, adding 17 variants and raising known SIgAD-associated variants to 26, supporting a polygenic common-variant etiology.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/leveraging-pleiotropy-identifies-common-variant-associations-with-selective-iga-deficiency/447666/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/leveraging-pleiotropy-identifies-common-variant-associations-with-selective-iga-deficiency/447666.png","ImageObject",300,407,{"name":92,"@type":93},"dabgoudw","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-08","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address in selective IgA deficiency genetics?","Question",{"text":112,"@type":113},"It addresses the lack of power in previous SIgAD studies to identify common-variant associations due to limited sample sizes, and the insufficient evidence for highly penetrant rare variants.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were new SIgAD-associated variants identified?",{"text":117,"@type":113},"The work first meta-analyzed two existing GWAS to find four novel common-variant associations. It then applied conditional false discovery rate, conditioning SIgAD meta-analysis on large asthma and rheumatoid arthritis GWAS and on its own serum IgA meta-analysis.",{"name":119,"@type":110,"acceptedAnswer":120},"How many SIgAD-associated variants does the study report after conditioning analysis?",{"text":121,"@type":113},"It increases the number of known SIgAD-associated variants to 26 by identifying an additional 17 variants through the pleiotropy-based conditional approach.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},447666,1791350611,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},3985747860484,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Europe PMC unders uthManuscripts Europe M eC und Author Manuscripts  \n| Europe PMC Funders Group\u003Cbr>Author Manuscript\u003Cbr>Clin Immunol. Author manuscript; available in PMC 2026 January 06. |\n| --- |\n| Published in final edited form as:\u003Cbr>Clin Immunol. 2024 November 01; 268: 110356. doi:10.1016/j.clim.2024.110356 .\u003Cbr>Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency\u003Cbr>Thomas W. Willis 1,4 , Effrossyni Gkrania-Klotsas2,3 , Nicholas J. Wareham2 , Eoin F. McKinney4,5 , Paul A. Lyons4,5 , Kenneth G.C. Smith6,7 , Chris Wallace 1,4,5\u003Cbr>1Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.\u003Cbr>2Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.\u003Cbr>3 Department of Infectious Diseases, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.\u003Cbr>4Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.\u003Cbr>5 Department of Medicine, University of Cambridge, Cambridge, UK.\u003Cbr>6Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.\u003Cbr>7 Department of Medical Biology, University of Melbourne, Melbourne, Australia.\u003Cbr>Abstract\u003Cbr>Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI) . Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 17 variants, increasing the number of known SIgAD-associated variants to 26 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD.\u003Cbr>Keywords\u003Cbr>immunoglobulin A; immunodeficiency; GWAS; pleiotropy\u003Cbr>This work is licensed under a BY 4.0 International license.\u003Cbr>Correspondence to: Thomas W. Willis; Chris Wallace.\u003Cbr>* [thomas.willis@mrc-bsu.cam.ac.uk](thomas.willis@mrc-bsu.cam.ac.uk); [cew54@cam.ac.uk](cew54@cam.ac.uk).\u003Cbr>Conflicts of Interest\u003Cbr>C.W. receives funding from GSK and MSD and is a part time employee of GSK. These companies had no input into this work. |\n\nEurope PMC unders uthManuscripts Europe M eC und Author Manuscripts  \nWillis et al. Page 2  \n1 Introduction  \nInborn errors of immunity (IEIs) comprise a group of 485 diseases characterised by immune dysfunction of genetic origin [1] . Selective IgA deficiency (SIgAD) is the most common of these disorders in Europeans. SIgAD is defined by a serum IgA level below 7mg/dL in individuals four years and older in whom serum IgG and IgM are normal, and for whomother causes of hypogammaglobulinaemia have been excluded [2]; some authors also allow for the presence of IgG subclass deficiency in SIgAD [3,4] . SIgAD has a prevalence in individuals of European ancestry between 1:300 and 1:1,200 [5] . Higher estimates have been  \nreported in Saudi Arabia (1:143) [6] and Nigeria (1:252) [7], but the disorder appears to  \nbe less common in East Asian ancestries such as Japanese (1:14,840) [8] and Han Chinese  \n(1:3,230) [9] .  \nThe fundamental defect in SIgAD is a deficiency in IgA production. IgA is the most abundant antibody in the body [10] and exists in monomeric and mainly dimeric forms in the serum and on the mucosae, respectively; other quaternary structures of secretory IgA, including trimers and tetramers, are known [11]. IgA is recognised as the principal antibody isotype in mucosal immunity in the respiratory, ga","cbCaitVDBooHh1VU","https://ap.wps.com/l/cbCaitVDBooHh1VU","pdf",1030752,34,"English","# Abstract\n# Introduction","[{\"question\":\"What problem does the study address in selective IgA deficiency genetics?\",\"answer\":\"It addresses the lack of power in previous SIgAD studies to identify common-variant associations due to limited sample sizes, and the insufficient evidence for highly penetrant rare variants.\"},{\"question\":\"How were new SIgAD-associated variants identified?\",\"answer\":\"The work first meta-analyzed two existing GWAS to find four novel common-variant associations. It then applied conditional false discovery rate, conditioning SIgAD meta-analysis on large asthma and rheumatoid arthritis GWAS and on its own serum IgA meta-analysis.\"},{\"question\":\"How many SIgAD-associated variants does the study report after conditioning analysis?\",\"answer\":\"It increases the number of known SIgAD-associated variants to 26 by identifying an additional 17 variants through the pleiotropy-based conditional approach.\"}]","Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency | PDF",1790722116,86]