Genetic determinants of complement activation in the general population
Damia Noce1, Luisa Foco2, Dorothea Orth-Höller3
1Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria.
Abstract:
Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement's genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways' genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.
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