Genetic determinants of complement activation in the general population
Damia Noce,
Luisa Foco,
Dorothea Orth-Höller,
Eva König,
Giulia Barbieri,
Maik Pietzner,
Dariush Ghasemi-Semeskandeh,
Stefan Coassin,
Christian Fuchsberger,
Martin Gögele,
Fabiola Del Greco M.,
Alessandro De Grandi,
Monika Summerer,
Eleanor Wheeler,
Claudia Langenberg,
Cornelia Lass-Flörl,
Peter Paul Pramstaller,
Florian Kronenberg,
Reinhard Würzner,
Cristian Pattaro
Affiliations
Damia Noce
Institute 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
Luisa Foco
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Dorothea Orth-Höller
Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; MB-LAB – Clinical Microbiology Laboratory, Franz-Fischer-Str. 7b, 6020 Innsbruck, Austria
Eva König
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Giulia Barbieri
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
Maik Pietzner
Computational Medicine, Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
Dariush Ghasemi-Semeskandeh
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Stefan Coassin
Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Christian Fuchsberger
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Martin Gögele
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Fabiola Del Greco M.
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Alessandro De Grandi
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Monika Summerer
Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Eleanor Wheeler
MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
Claudia Langenberg
Computational Medicine, Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany
Cornelia Lass-Flörl
Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Peter Paul Pramstaller
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Florian Kronenberg
Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; Corresponding author
Reinhard Würzner
Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; Corresponding author
Cristian Pattaro
Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Corresponding author
Summary: 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.
