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.
摘要：
补体是一种基本的先天免疫应答成分。其改变与严重的全身性疾病相关。为了阐明补体的遗传基础，我们对经典（CP）的功能活性进行全基因组关联研究，凝集素（LP），和替代（AP）补体途径在南蒂罗尔合作健康研究中的研究（n=4,990）。我们确定了七个基因座,包括13个独立的，位于补体基因（CFHR4，C7，C2，MBL2）和非补体基因（PDE3A，TNXB,ABO),解释高达74%的补体途径遗传遗传性，并暗示MBL2与LP相关的远程单倍型。双样本孟德尔随机化分析，由转录组和蛋白质组共同定位支持，确认已知的因果途径，建立互补内反馈回路，并暗示ABO在LP上的因果关系以及CFHR2和C7在AP上的因果关系。LP会导致collectin-11和KAAG1水平以及口腔溃疡的风险。这些结果建立了一个全面的资源来研究补体在人类健康中的作用。
