Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome (original) (raw)

2023, Nature Communications

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations. Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is a rare disease of the glomerular filtration barrier. Its incidence ranges from 1.15-16.9 cases in every 100,000 children, occurring most frequently in South Asian populations 1. pSSNS causes massive proteinuria and increases the risk of thromboembolism, sepsis, and progression to chronic kidney disease (CKD)/end-stage kidney disease (ESKD) 2-7. And those progressing to ESKD have increased odds of recurrent NS in their allograft 8. pSSNS is impactful across the lifespan-31-50% of those affected have relapses in adulthood 9. Much of pSSNS's morbidity is related to side effects of the non-specific immunosuppressants which allow some to achieve remission of their proteinuria 7, 10-17. Despite intensive investigation, there are no known monogenic forms of pSSNS to illuminate its pathobiology. However, we know that immune dysregulation is a major contributor 18,19. But determining causal immune factors via case-control studies of cytokines profiles, cell types, and transcriptomic signatures is challenging. The dynamic responses of the immune system at different disease stages and to various stimuli make it difficult to determine whether observed differences are causal, correlated, or due to independent biological/