%0 Journal Article
%T Genetic determinants of complement activation in the general population.
%A Noce D
%A Foco L
%A Orth-Höller D
%A König E
%A Barbieri G
%A Pietzner M
%A Ghasemi-Semeskandeh D
%A Coassin S
%A Fuchsberger C
%A Gögele M
%A Del Greco M F
%A De Grandi A
%A Summerer M
%A Wheeler E
%A Langenberg C
%A Lass-Flörl C
%A Pramstaller PP
%A Kronenberg F
%A Würzner R
%A Pattaro C
%J Cell Rep
%V 43
%N 1
%D 2024 01 23
%M 38159276
暂无%R 10.1016/j.celrep.2023.113611
%X 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.