Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined PADJ = 1.15 × 10−6, OR 1.332 (1.187–1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10−8, OR 1.541 (1.324–1.796); males: PADJ = 0.382, OR 1.084 (0.905–1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.
We thank all patients and control individuals for their participation in the study, Kerstin Meier and Jürgen Kaschkötö (Institute of Human Genetics, University of Regensburg) for technical support, and Lars G. Fritsche (Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan) and Thomas Winkler (Institute of Epidemiology, University of Regensburg, Regensburg) for help with computational tools and data analysis. This study was supported partly by the Deutsche Forschungsgemeinschaft (WE 1259/19-1 and WE 1259/19-2 to BHFW), the Alcon Research Institute (to BHFW and RA), by grants from the National Eye Institute/NIH EY013435 and EY019007 (to RA); the Macula Vision Research Foundation (to RA); an unrestricted grant to the Department of Ophthalmology, Columbia University, from Research to Prevent Blindness, Inc. (to RA), and the Guide Dogs for the Blind Association UK (2008-5a) Macular Disease Society (to US, GS, GJM).
Data Availability StatementElectronic supplementary material is available within the article links
- Age-related macular degeneration
- Canonical DAPL1 isoforms
- Death-associated protein-like 1, DAPL1
- Genetic association study