{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T13:50:19Z","timestamp":1792417819206,"version":"4.4.0"},"reference-count":25,"publisher":"Rockefeller University Press","issue":"1","license":[{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2027,1,4]]},"abstract":"<jats:p>Validating weak gene\u2013disease associations requires statistical support from large case\u2013control studies. In contrast, strong (e.g., monogenic) gene\u2013disease associations may be established from relatively few affected individuals, when independent orthogonal evidence converges. Here, we examine four publications associating heterozygous variants in five genes\u2014TNIP1, P2RY8, BLK, BANK1, and SH2B3\u2014with autoimmune disease (predominantly systemic lupus erythematosus [SLE]). While we do not dispute the molecular findings of these studies, we do not accept the proposed disease associations, which lack case\u2013control evidence and where high minor allele frequencies in non-disease populations, indicate that the genotypes are far too common to represent Mendelian disease alleles. Additionally, 8 of 18 alleles were searchable in UK Biobank, and none showed enrichment in SLE. Until further evidence emerges, caution is warranted in ascribing disease association to heterozygous genotypes in TNIP1, P2RY8, BLK, BANK1, and SH2B3, and linkage to patients in clinical pedigrees should not be taken as inferring a monoallelic inborn error of immunity.<\/jats:p>","DOI":"10.70962\/jhi.20260099","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T13:10:23Z","timestamp":1792415423000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Disease associations for rare immune genetic variants require statistical or rule-based support"],"prefix":"10.70962","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2057-3968","authenticated-orcid":true,"given":"Paul E.","family":"Gray","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03t52dk35","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, Western Sydney University 1 , Sydney,","place":["Australia"]},{"id":[{"id":"https:\/\/ror.org\/02tj04e91","id-type":"ROR","asserted-by":"publisher"}],"name":"Sydney Children\u02bcs Hospital 2 Department of Immunology and Infectious Diseases, , Sydney,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-5180","authenticated-orcid":true,"given":"Stuart G.","family":"Tangye","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01b3dvp57","id-type":"ROR","asserted-by":"publisher"}],"name":"Garvan Institute of Medical Research 3 , Sydney,","place":["Australia"]},{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Clinical Medicine, UNSW Sydney 4 Faculty of Medicine and Health, , Sydney,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4662-0024","authenticated-orcid":true,"given":"Edwin P.","family":"Kirk","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Clinical Medicine, UNSW Sydney 4 Faculty of Medicine and Health, , Sydney,","place":["Australia"]},{"id":[{"id":"https:\/\/ror.org\/02tj04e91","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Clinical Genetics, Sydney Children\u02bcs Hospital 5 , Sydney,","place":["Australia"]},{"id":[{"id":"https:\/\/ror.org\/01b3dvp57","id-type":"ROR","asserted-by":"publisher"}],"name":"Australia Garvan Institute of Medical Research 6 NSW Health Pathology Randwick Genomics Laboratory, , Sydney,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"2026101909101759400_bib1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.5808\/GI.2012.10.2.117","article-title":"Sample size and statistical power calculation in genetic association studies","volume":"10","author":"Hong","year":"2012","journal-title":"Genomics Inform."},{"key":"2026101909101759400_bib2","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1084\/jem.20140520","article-title":"Guidelines for genetic studies in single patients: Lessons from primary immunodeficiencies","volume":"211","author":"Casanova","year":"2014","journal-title":"J. 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