Medical records-based genetic studies of the complement system

Background Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts. Methods We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network. Results InaGWAS forC3levels in3949individuals,wedetectedtwogenome-widesignificant loci: Chr.1q31.3 (CFH locus; rs3753396-A; b50.20; 95% CI, 0.14 to 0.25; P51.52x10-11) and chr.19p13.3 (C3 locus; rs11569470-G; b50.19; 95% CI, 0.13 to 0.24; P51.29x10-8). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; b50.40; 95% CI, 0.34 to 0.45; P54.58x10-35). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (b520.36; 95% CI, 20.42 to 20.30; P52.98x10-22) and C4-AL-BS (b50.25; 95% CI, 0.21 to 0.29; P58.11x10-23). Overall, C4 levels were strongly correlatedwith copy numbers ofC4A andC4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation. Conclusions We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronicmedical records.Genetic variants regulating C3 andC4 levels have large effects andmultiple clinical correlations across the spectrum of complement-related diseases in humans.