Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

Abstract

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry matched controls revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

“…This binds to and stabilises C3 convertase, leading to the activation of the alternative complement factor pathway and excessive consumption of C3 (Misra et al, 2004;Savage et al, 2009). Increased activity of C3 convertase activity has also been proposed as a risk for developing AMD (Helgason et al, 2013;Seddon et al, 2013;Zhan et al, 2013). High-risk alleles in CFH similarly act in this pathway.…”

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

“…Among these correlations, mutations that alter the C-terminal region of FH are prototypical of aHUS, 7-9 whereas the Y402H polymorphism in SCR7 of FH is a unique risk factor for AMD [10][11][12][13] and complete FH deficiency or homozygous mutations in the N-terminal region of FH associate with C3G. 14,15 In this context, the association of the C-terminal FH-R1210C mutation with aHUS, 16 AMD, [17][18][19] and C3G 2 0 challenges these genotypephenotype correlations, suggesting previously unrecognized pathogenic links between these disorders. Here, we performed experiments to reveal the molecular basis of these associations and to identify what determines the disease outcome in FH-R1210C carriers.…”

Improved Ancestry Estimation for both Genotyping and Sequencing Data using Projection Procrustes Analysis and Genotype Imputation

“…We further demonstrate that genotype imputation on the ancestry reference panel, in combination with projection Procrustes analysis, can substantially improve estimation of fine-scale European ancestry for both exome chip genotyping data and low-coverage sequencing data. Using targeted sequencing data from our AMD study, 8 we show that the improvement of ancestry estimation is more evident for samples that have extremely low coverage in the off-target regions and for which ancestry cannot be accurately estimated via LASER 1.0. 22 Overall, the novel algorithm of LASER 2.0 enables us to obtain accurate genetic ancestry information in several challenging settings where LASER 1.0 doesn't work well, including finer-scale ancestry with extremely low coverage sequencing data or with exome chip genotypes.…”

“…22 We have applied LASER 1.0 to facilitate identification of additional ancestry-matched controls from public resources to increase statistical power in a targeted sequencing study of age-related macular degeneration (AMD). 8 However, estimation of fine-scale ancestry within Europe remains challenging when the sequencing depth is <0. 13.…”

“…4,5 Applications of targeted sequencing and exome chip genotyping have discovered several disease-associated rare coding variants, leading to important biological insights for several complex diseases. [4][5][6][7][8][9] Control of population stratification is important for large-scale genetic association studies to avoid spurious association signals caused by ancestry difference in the study sample. [10][11][12][13] Population structure can confound genetic association tests even when all study subjects are Europeans, 14 highlighting the importance of estimating finescale ancestry.…”