Genetics of membranous nephropathy

Autoimmune membranous nephropathy (AMN) is a rare kidney disease. The genetics of AMN have been partially elucidated and confirmed the role of phospholipase A2 receptor-1 (PLA2R1) and HLA. The functional effect of the genetic variations is not fully understood. This thesis investigates these unexplored genetic aspects utilising a range of methodologies and unique cohorts. Analysing genomic sequencing data of PLA2R1 in 335 AMN patients identified 109 strongly associated variants; 9 with a very strong association, p-value <10-50. In a larger cohort of 1158 European AMN patients, the findings from previous GWAS were confirmed with a strong association with HLA-DQA1, HLA-DRB1 and PLA2R1. No associations were found on a genome wide scale with clinical correlates of disease such as proteinuria, sex, and age. HLA typing by imputation in 372 anti-PLA2R1 antibody positive and uniquely 32 antithrombospondin type-1 domain-containing 7A (THSD7A) antibody positive AMN confirmed the dominant HLA type in European AMN as HLA-DRB1*03:01 and HLADQA1*05:01; replicating previous studies. No statistically significant HLA type was identified for anti-THSD7A AMN. Anti-PLA2R1 AMN has a different genetic risk than anti-THSD7A and anti-contactin AMN as determined by the genetic risk score (GRS), and this can help differentiate between them. Interestingly, 33% of dual antibody negative AMN is likely to be anti-PLA2R1 AMN. AMN patients with a higher genetic risk have a younger age of onset. In a rare, undescribed cohort of 15 non-familial paediatric cases of AMN the GRS proved that these individuals did not have the same genetic risk factors as anti-PLA2R1 AMN. Finally, the genetic risk of AMN in UK Biobank Europeans is 0.8%. Even though there is a high genetic risk for AMN this does not mean this proportion of individuals will develop AMN. In conclusion, this thesis highlights important differences between antibody status groups, confirms previous GWAS findings and reports unique features about rare AMN cohorts