Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

Abstract

Background: Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits.

Methods: For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression.

Results: Of the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values < 0.01, p values from < 1.0 × 10^-16 to 1.9 × 10^-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 × 10^-7 to 3.0 × 10^-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis.

Conclusions: We demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common.

Keywords: AMD; Age-related macular degeneration; Complex traits; GRS; Genetic association studies; Genetic risk scores; Shared genetics.

Fig. 1

Pairwise correlation between selected genetic scores. The color key represents the strength of the correlation between pairs of genetic scores, estimated as the correlation coefficient. The numbers on the bottom half of the graph indicate the correlation coefficient. The numbers in the top half indicate the statistical significance of the observed correlation coefficient (*Q-value < 0.01, **Q-value < 0.001, ***Q-value < 0.0001). The abbreviations used for each trait are listed in Additional file 2: Table S1

Fig. 2

Association of 60 genetic scores with AMD. Logistic regression models, adjusted for age, gender, the first two principle components computed from the genotypes as well as DNA source were fitted for 60 genetic scores of selected complex diseases and traits. LOR (squares) and 95% confidence intervals (horizontal lines) obtained for each genetic score are plotted. *Q-value < 0.01, **Q-value < 0.001, ***Q-value < 0.0001

Fig. 3

Relationship between complex diseases/traits and AMD based on significant genetic score associations. Nodes represent diseases or traits and are colored according to uniform color scheme (see also Fig. 2 and Additional file 2: Table S1). The size of each node represents the effect size of the association with AMD. Diseases and traits within distinct disease categories (see also Fig. 2) are connected with lines colored according to the respective disease category. Lines connecting AMD and diseases/traits indicate the direction of the association with red lines indicating an adverse association and blue lines representing protective associations. Gray lines depict interactions according to literature which could not be confirmed by genetic scores or were not investigated within this study. The numbers in brackets indicate the references which either support or dispute the respective interaction. The colors of the numbers indicate whether the cited literature reported an adverse (red) or a protective (blue) interaction. In case a finding is novel, no literature reference is presented on a connection between nodes