Abstract
Late-stage age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly with a complex etiology. The most important non-modifiable risk factors for onset and progression of late AMD are age and genetic risk factors, however, little is known about the interplay between genetics and age or sex. Here, we conducted a large-scale age- and sex-stratified genome-wide association study (GWAS) using 1000 Genomes imputed genome-wide and ExomeChip data (>12 million variants). The data were established by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) from 16,144 late AMD cases and 17,832 controls. Our systematic search for interaction effects yielded significantly stronger effects among younger individuals at two known AMD loci (near CFH and ARMS2/HTRA1). Accounting for age and gene-age interaction using a joint test identified two additional AMD loci compared to the previous main effect scan. One of these two is a novel AMD GWAS locus, near the retinal clusterin-like protein (CLUL1) gene, and the other, near the retinaldehyde binding protein 1 (RLBP1), was recently identified in a joint analysis of nuclear and mitochondrial variants. Despite considerable power in our data, neither sex-dependent effects nor effects with opposite directions between younger and older individuals were observed. This is the first genome-wide interaction study to incorporate age, sex and their interaction with genetic effects for late AMD. Results diminish the potential for a role of sex in the etiology of late AMD yet highlight the importance and existence of age-dependent genetic effects.
Highlights
Age-related macular degeneration (AMD) is a degenerative disorder of the central retina and late stage AMD represents the leading cause of irreversible vision loss in the elderly population of western societies [1,2,3]
To understand whether genetic effects for late AMD are modulated by age, we conducted agestratified Firth-corrected logistic regression analyses on AMD for each of the 1000 Genomesimputed variants in the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) data set (16,144 patients and 17,832 controls of European ancestry, Online Methods)
We find modulating effects of age on late AMD genetics, identifying three variants in the CFH and ARMS/HTRA1 loci with stronger effects in younger individuals, but no evidence for effects that are protective in one age-group and adverse or zero in the other
Summary
Age-related macular degeneration (AMD) is a degenerative disorder of the central retina and late stage AMD represents the leading cause of irreversible vision loss in the elderly population of western societies [1,2,3]. Late AMD can present as a neovascular complication, characterized by choroidal/sub-retinal neovascularization (NV), or an atrophicform, known as geographic atrophy (GA) of the retinal pigment epithelium (RPE) [2,3]. Both conditions lead to photoreceptor loss, the pathogenesis is only imprecisely understood and therapeutic options are still limited [2,3,4]. Adequately powered systematic genome-wide searches for gene-environment interaction (GxE) for AMD are lacking
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