Disease associations of natural killer (NK) cell KIR gene content variation in 352,783 Finns

Allelic, gene presence/absence, and gene-copy number variations in the KIR genes encoding Natural Killer (NK) cell surface receptors have been reported to be associated in case-control studies with infectious and autoimmune diseases, and relapse after stem cell transplantation. To understand more comprehensively the role of KIR gene presence/absence variation and HLA-KIR interactions in disease susceptibility, we imputed from genome SNP data the presence and absence of 10 KIR genes in the FinnGen cohort. The cohort consists of 352,783 Finns with extensive phenotypes from the national health registries. We tested associations between 762 FinnGen phenotypes and presence/absence variation based on imputation of KIR genes using 5,900 SNPs located in the KIR genomic segment. Our results provide a platform to query HLA-KIR associations in a large population cohort. We found 13 phenotype - KIR gene or KIR - HLA C combination associations with false discovery rate < 0.05. These results differ from the very high number of associations between HLA alleles and diseases reported earlier in the FinnGen cohort. Five of the 13 significant associations included malignant phenotypes, e.g., melanoma, thyroid gland neoplasm, and haematopoietic malignancy, supporting the essential role of NK cells in controlling malignancy.