Significance Dysregulation of the alternative complement pathway due to impaired binding of complement factor H (CFH) to self-ligands or altered self-ligands (e.g. malondialdehyde [MDA]-modified molecules) involved in homeostasis can promote the development of complement-related diseases, such as age-related macular degeneration (AMD). We identified, in an unbiased GWAS approach, that common genetic variants within the CFH gene family (rs1061170 and the deletion of the complement factor H-related protein 1 and 3 genes [ CFHR3 and CFHR1 ]) act as major modulators of CFH recruitment and its ability to regulate complement on MDA-epitopes. These findings demonstrate the importance of the genetic status within the CFH/CFHR3/CFHR1 locus in tissue homeostasis and provide a mechanistic explanation as to why deletion of CFHR3/ CFHR1 is protective in AMD development.