Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania

Abstract

The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-61*02 allele. We show each copy of IGHV4-61*02 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27-1.61, P=4.1 × 10^-9). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.

Figure 1. Oceanian study population.

(a) Approximate location where genotyped cases (red) and controls (black) were sampled. (b) Projection of the samples on to the first and second (left) and first and third (right) principal components (PCs) of genetic variation coloured by self-reported ancestry (MEL, Melanesians; POL, Polynesian; IND, Fijian Indian; MIX, Mixed and other) with cases indicated by empty squares and controls by empty diamonds. Selected samples from the Human Genome Diversity Project Panel (NGH, Papuan; EAS, South East Asian; EUR, European; CSA, Central South Asian) are superimposed for comparison and indicated by filled circles. (c) Estimates of admixture proportions from four source populations grouped by self-reported ancestry, with selected samples of Papuan and European ancestry shown at the far left and right, respectively, for comparison.

Figure 2. Genome-wide meta-analysis for RHD susceptibility.

For each variant, the negative common logarithm of the P value from an inverse-variance weighted fixed-effects meta-analysis is plotted against genomic position. The blue horizontal line indicates suggestive significance (FE meta-analysis, P=10⁻⁵) and the red horizontal line indicates genome-wide significance (FE meta-analysis, P=5 × 10⁻⁸).

Figure 3. Association of the IGHV4-61 locus with RHD susceptibility.

(a) For each variant in the 99% credible set, the common logarithm of the Bayes' factor is plotted against genomic position. Variants are coloured by linkage disequilibrium with the most associated variant averaged across the entire data set (estimated r²: dark blue, 0–0.2; light blue, 0.2–0.4; green, 0.4–0.6; yellow, 0.6–0.8; red, 0.8–1.0). A vertical blue line indicates the position of the four nonsynonymous variants in IGHV4-61 and locations of expressed IGH gene segments are indicated by blue rectangles below the x axis. (b) Forest plot for the IGHV4-61*02 allele under an additive genetic model with association statistics from LMM analysis in each strata combined by FE meta-analysis. Individual and combined odds ratio estimates with confidence intervals are shown on a logarithmic scale. (c) Structural model of an antibody that includes the IGHV4-61 heavy variable domain (Protein Databank 4FQQ) showing both heavy (blue) and light (white) chains with both the first (CDR-H1, green) and second (CDR-H2, violet) heavy chain complementarity determining loops and the heavy chain interface framework loop (HIFL, red) highlighted. The positions that distinguish IGHV4-61*01 from IGHV4-61*02 are shown as spheres labelled with the amino acids found in IGHV4-61*01.