{Reference Type}: Journal Article
{Title}: Genetic determinants of complement activation in the general population.
{Author}: Noce D;Foco L;Orth-Höller D;König E;Barbieri G;Pietzner M;Ghasemi-Semeskandeh D;Coassin S;Fuchsberger C;Gögele M;Del Greco M F;De Grandi A;Summerer M;Wheeler E;Langenberg C;Lass-Flörl C;Pramstaller PP;Kronenberg F;Würzner R;Pattaro C;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 1
{Year}: 2024 01 23
暂无{DOI}: 10.1016/j.celrep.2023.113611
{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.