Abstract
Background: Complement is a fundamental part of the innate immune response. Its alterations are associated with severe systemic diseases.
Methods: To illuminate the complement’s genetic underpinnings, we conducted genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways using serum samples, stored at –80_C since the day of collection, analyzed with the WIESLAB_ complement system screen kit (SVAR, Malmö, formerly Wieslab AB, Lund, Sweden) according to manufacturers’ instructions in the Cooperative Health Research in South Tyrol (CHRIS) study (n=4990).
Results: We identified 7 loci that included 13 independent, pathway-specific variants (p<5_10-8) located in or near complement (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining 12%, 18% and 73% of CP, AP and LP’s genetic heritability, respectively. Variants were associated with inflammatory, autoimmune and coagulation disorders and >400 proteins. Transcriptome- and proteome-wide colocalization analyses combined with two-sample Mendelian randomization confirmed known causal pathways, established within-complement feedback loops, and implicated causality of ABO on LP and of CFHR2 and C7 on AP. LP showed causal effects on collectin-11 and KAAG1 levels and mouth ulcers’ risk. Conclusion: These results build a comprehensive resource to investigate the role of complement on human health.