Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD)

Abstract

Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of CYP1A1, a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1.

Seed sequence polymorphism rs2168518 and allele-specific target gene regulation of hsa-miR-4513

“…As a consequence, small allele-specific regulatory effects may only become apparent with an increase in target gene expression or by effects accumulating with age. This would also fit with the associations found for hsa-miR-4513 and its seed polymorphism rs2168518 with age-related phenotypes such as cancer ( 8–11 ), cardiovascular conditions ( 12–15 ) and age-related macular degeneration ( 15 , 16 ). In summary, allele-specific regulation of CDKN2A by hsa-miR-4513-A is a promising mechanism that could explain the association of the miRNA locus with seemingly unrelated age-related pathologies.…”

“… Results of literature text searches relating allele-specific hsa-miR-4513 target genes with phenotypes. Various phenotypes have been reported in the literature to which hsa-miR-4513 or its seed polymorphism rs2168518 have been linked, including cancer ( 8–11 , 17 ), cardiovascular phenotypes ( 12–15 ), age-related macular degeneration ( 15 , 16 ), diabetes ( 12 ), metabolic products in urine ( 15 ) and several lipid traits ( 12 ). The online databases OMIM ( 19 ) and MGI ( 22 ) were searched to assign allele-specific target genes to individual phenotype groups by specific keywords defined as follows: ‘cell proliferation’ or ‘cell death’ (cancer), ‘cardiovascular system’ (cardiovascular phenotypes), ‘vision/eye’ (age-related macular degeneration), ‘cellular glucose’ or ‘insulin resistance’ (diabetes), ‘homeostasis/metabolism’ and ‘renal/urinary system’ (metabolic products in urine) and ‘lipid binding’ (lipid traits).…”

“…Another explanation for the associations detected at this locus could be an expression quantitative trait locus, where a polymorphism has a regulating effect on the expression of nearby genes, eventually by altering a transcription factor binding site. To this end, several studies have reported regulatory effects of rs2168518, or of highly linked variants, on several genes located within the same locus as hsa-miR-4513, including the miRNA host gene CSK ( 12 , 15 , 39–41 ). Due to the exogenously increased miRNA expression following our study design, it is difficult to speculate about a possible co-expression of hsa-miR-4513 and its host gene CSK and its consequences.…”

“…Hsa-miR-4513 is an exemplary miRNA harboring a common polymorphism (rs2168518) in its seed region and was recently reported to be overexpressed in several cancer cell lines ( 8–11 ) as well as in cancer tissue ( 11 ). In addition, rs2168518 was associated with several clinically relevant traits and diseases, including cardiovascular phenotypes ( 12–15 ), fasting glucose and lipid traits ( 12 ), age-related macular degeneration ( 15 , 16 ) and different metabolic products in urine ( 15 ). Moreover, rs2168518 is suggested as possible biomarker to predict lung adenocarcinoma survival rates after treatment with tyrosine kinase inhibitors ( 17 ).…”

Association of neovascular age-related macular degeneration with migraine

“…This significant association was evident in both nonexudative and exudative AMD subgroups 7 . The relationship between AMD and cardiovascular disease is supported by genetic studies that the pleiotropic 15q24.1 association signal may have a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1 8 . Further genetic evidence from a total of 33,526 individuals predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium showed that increasing HDL-cholesterol (particularly via CETP inhibition) is a causal risk factor for AMD and that increasing HDL-cholesterol will increase AMD risk 9 .…”