Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in ageing societies, triggered by both environmental and genetic factors. The strongest genetic signal for AMD with odds ratios of up to 2.8 per adverse allele was found previously over a chromosomal region in 10q26 harboring two genes, ARMS2 and HTRA1, although with little knowledge as to which gene or genetic variation is functionally relevant to AMD pathology. In this study, we analyzed rare recombinant haplotypes in 16,144 AMD cases and 17,832 controls from the International AMD Genomics Consortium and identified variants in ARMS2 but not HTRA1 to exclusively carry the AMD risk with P-values between 1.0 × 10^-773 and 6.7 × 10^-5 This now allows prioritization of the gene of interest for subsequent functional studies.

Keywords: ARMS2/HTRA1 gene locus; age-related macular degeneration; genetic association studies; haplotypes; linkage disequilibrium.

Figure 1

Delineating associated haplotypes at the ARMS2/HTRA1 locus. Shown are 13 haplotypes defined by 25 variants that were either correlated with the lead variant rs3750846 (R² > 0.8) or in the 99% credible set of associated variants (Fritsche et al. 2016) (see also Table 1). P-values are given based on a logistic regression model including H1–H12 as covariates and H0 carrying exclusively nonrisk alleles as reference. AMD risk-increasing alleles are colored in red and the protective alleles in blue. In the case in which a haplotype is carrying the risk-increasing allele of a variant but is not significantly associated with AMD, this variant is regarded not to be associated with disease risk. Similarly, if a haplotype carrying the protective variant allele is increasing the risk for the disease, we concluded that this variant is not associated with AMD risk. The minimal set of risk-associated variants (gray box) includes 13 variants not excluded by the haplotype analysis and located exclusively at the immediate ARMS2 locus. Thin dark blue boxes represent the UTR; thick dark blue boxes represent the coding region of ARMS2 as well as the first exon of HTRA1. Gene sizes and relative positions are not to scale. Intronic sequences are given by dark blue arrows indicating the direction of transcription. Each square as part of a haplotype represents a single variant, ordered by chromosomal position from centromere (left) to telomere (right) (see also Table 1). Also shown is the number of observed best-guess haplotypes (N), the odds ratio (OR), and 95% confidence intervals (95% C.I.) as well as the frequency of the best-guess haplotypes H0–H12 in cases and controls.