Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

Abstract

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10^-8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10^-9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10^-8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Figure 1. Genome-wide association plot for the Meningococcal meta-analysis between the Spanish and UK MD collections.

The Y-axis denotes the strength of the association (−log10 P-value) for each SNP marker. The X-axis denotes individual chromosomes. The horizontal lines denote significant (P-value = 5 × 10⁻⁸) and suggestive (P-value = 10⁻⁵) evidence of association with disease. The red dot is the top SNP (rs193053835) with the minimal P-value, and the green dot is the functional candidate SNP (rs1065489).

Figure 2. SNPs in the CFHR genes region were plotted according to its location in the genome (X-axis) against the combined meta-analysis −log10 P-value in the Y-axis.

The candidate SNP; rs1065489 is denoted as the purple circle, whereas red circles represent SNPs in LD (r² ≥ 0.8) with rs1065489. Recombination rates and LD values were plotted based on the 1000 Genomes European 2012 reference, in genome build hg19. See also Supplementary Data Figures S8 that covers the CFHR3 and CFHR1 regions using a call rate filter >80%.