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Peer-reviewedCC BYJournal of human immunity

Disease associations for rare immune genetic variants require statistical or rule-based support.

  • Paul E Gray1,2
  • Stuart G Tangye3,4
  • Edwin P Kirk4,5,6
6 affiliations
  1. 1School of Medicine, Western Sydney University , Sydney, Australia.
  2. 2Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, Australia.
  3. 3Garvan Institute of Medical Research , Sydney, Australia.
  4. 4Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, Sydney, Australia.
  5. 5Centre for Clinical Genetics, Sydney Children's Hospital , Sydney, Australia.
  6. 6NSW Health Pathology Randwick Genomics Laboratory, Australia Garvan Institute of Medical Research, Sydney, Australia.
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Abstract

Validating weak gene-disease associations requires statistical support from large case-control studies. In contrast, strong (e.g., monogenic) gene-disease 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-TNIP1, P2RY8, BLK, BANK1, and SH2B3-with 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-control 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.

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Cite

BibTeXRIS
BibTeX
@article{gray2026disease,
  title = {{Disease associations for rare immune genetic variants require statistical or rule-based support.}},
  author = {Paul E Gray and Stuart G Tangye and Edwin P Kirk},
  journal = {Journal of human immunity},
  year = {2026},
  month = oct,
  doi = {10.70962/jhi.20260099},
  url = {https://europepmc.org/article/MED/42895470},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Disease associations for rare immune genetic variants require statistical or rule-based support.
AU  - Paul E Gray
AU  - Stuart G Tangye
AU  - Edwin P Kirk
PY  - 2026
DA  - 2026/10/19
JO  - Journal of human immunity
DO  - 10.70962/jhi.20260099
UR  - https://europepmc.org/article/MED/42895470
AB  - Validating weak gene-disease associations requires statistical support from large case-control studies. In contrast, strong (e.g., monogenic) gene-disease 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-TNIP1, P2RY8, BLK, BANK1, and SH2B3-with 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-control 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.
SN  - 3065-8993
ER  -