Abstract
Alterations of the complement system (CS), which is a fundamental part of the innate immune response, are associated with both rare and common human diseases. The CS is activated via three distinct pathways: classical (CP), mannose-binding lectin (LP), and alternative (AP) pathways. No hypothesis-free genome-wide screen of the three CS pathways has been conducted so far. We conducted genome-wide
association studies of the functional activity of CP, LP, and AP in the Cooperative Health Research in South Tyrol (CHRIS) study (n=4,990). We identified seven loci, including 13 independent and pathway-specific variants (p<5×10-8) located in or near CFHR4, C7, C2, and MBL2 (known CS genes) and PDE3A, TNXB, and ABO (novel genes). Variants were associated with inflammatory, autoimmune, and coagulation disorders and >400 proteins. We conducted transcriptome- and proteome-wide colocalization analyses based on state-of-the-art datasets, in combination with two-sample Mendelian randomization analysis. We identified three types of results: (1) confirmation of known causal pathways (e.g.: causal role of MBL2 on LP); (2) identification of within-CS feedback loops (e.g.: between AP and complement 7); and (3) dentification of novel causal pathways, including: the causal role of ABO protein levels on LP (p value=1.1×10-10; MR-Egger intercept not significant); a causal effect of LP on collectin-11 ( p value=6.3×10-44; heterogeneity p value, Phet=0.46) and KAAG1 (p value=9.0×10-25; Phet=0.27) levels;
a causal effect of LP on mouth ulcers’ risk (p value=9.5×10-6; Phet=0.71). These results depict a first, comprehensive and unbiased map of the role of CS on human health.