Genome-Wide Association Study for Idiopathic Nephrotic Syndrome Identifies Susceptibility Loci Across the Lifespan, Response to Therapy, and Genetic Ancestry

Résumé fourni par la source

Background: The polygenic background of idiopathic nephrotic syndrome (INS) remains elusive: while previous genome-wide association studies (GWAS) identified risk loci for pediatric steroid sensitive nephrotic syndrome (pSSNS), the genetic architecture across different ages of onset and treatment responses is unclear. Here, we conducted a GWAS to characterize the polygenicity of INS across genetic ancestries, age of onset and treatment response. Methods: This study included 7610 INS cases, across genetic ancestries, ages of onset, and treatment responses, and 29342 controls. The case distribution were: pSSNS (N=3940), aSSNS (N=715), pSRNS (N=1195), aSRNS (N=1449). 70.4% of SRNS cases had paired sequencing data to extract Mendelian FSGS variants. We performed ancestry-specific GWAS on all cases, followed by stratified analyses by age of onset and therapy response. We then repeated these analyses after excluding 758 cases with likely pathogenic variants in FSGS genes, pathogenic CNVs or APOL1 high-risk genotypes (6787 cases and 28934 controls). We used PLINK2, METAL and MR-MEGA for analysis. Results: Metanalysis of INS irrespective of age of onset and therapy response showed association with HLA-DQB1(P=2.60x10-97,OR=2.11), and APOL1, driven by individuals of recent African ancestry(P=8.85x10-51,OR=2.91). Meta-analysis of pSSNS GWASs retrieved all 12 known loci and identified additional 9 new significant loci: chr3p13 (P=1.69x10-14), chr22q12.3 (P=1.84x10-13), chr17q21.1 (P=7.43x10-11), chr12p13.31 (P= 1.26x10-8), chr4q27 (P= 2.85x10-8), chr1q32.1 (P= 4.49x10-8), chr2q31.2 (P =2.97x10-10), chr7p14.1 (P=1.15x10-8), chr1q25.1 (P=3.55x10-8). Non-Mendelian pSRNS showed a strong immune signature with significant association to HLA-DQB1 (P=8.27x10-16, OR=1.77). Conclusion: Our GWAS identified novel candidate loci for INS, including pleiotropic risk alleles that predispose to NS across sub-phenotypes, and loci specific to ancestry, age of onset, and response to therapy. Many loci suggest drug targets with existing treatments possibly suggesting indication expansions and genetic-supported therapies. Funding: NIDDK Support, Other U.S. Government Support

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.