Unravelling the complex genetics of age-related macular degeneration The International AMD Genomics Consortium (IAMDGC). V. Cipriani1,2,3 on behalf of the International AMD Genomics Consortium (IAMDGC) 1) UCL Institute of Ophthalmology, University College London, London, United Kingdom; 2) Moorfields Eye Hospital, London, United Kingdom; 3) UCL Genetics Institute, London, United Kingdom.

   Background Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. AMD susceptibility is influenced by multiple environmental and genetic factors. To accelerate the discovery in the complex genetics of AMD, the International AMD Genomics Consortium (IAMDGC) has carried out the largest genotyping of rare and common variation ever conducted on AMD. Methods A large set of predominantly late AMD cases (N26K) and age-matched controls (N22K) were gathered from 26 studies and centrally genotyped on the same custom genome-wide array (250K tag-SNPs + 40K AMD variants) enriched for 225K common and rare exonic variants. Single-variant, forward conditional, haplotype-based tests and pathway analyses were performed on genotyped and 1000 Genomes-based imputed variants. We report results from primary analysis on unrelated late cases and controls of European ancestry. Results Single-variant association tests on 16,144 late AMD cases and 17,832 controls and 12M genotyped and well-imputed variants confirmed 18 of the 19 established AMD loci (Fritsche et al., Nat Genet, 2013). Genome-wide significance (P5x10-8) was observed for common variants at 16 novel loci (OR range=0.7-1.5; AUC score=0.58). Conditional tests culminated in a set of 57 common and rare independently associated variants (up to 36% of disease variance explained) with multiple signals within 10 known loci, e.g. CFH, C2/CFB, C3, COL8A1 and RAD51B. Heterozygotes for the common Y402H haplotype had variable risk (OR range=0.2-7.1) compared to homozygotes, and rare CFH haplotypes without the R1210C variant showed risk that was not significantly different from the Y402H haplotype. Sub-phenotype analyses revealed loci with different effects on the dry and wet form of the disease. Enrichment of pathways beyond the known complement cascade was observed, e.g. lipid metabolism. Discussion The IAMDGC has carried out the largest discovery of rare and common variants for AMD that has already resulted in an outstanding yield of 16 novel loci. Ongoing fine mapping analyses suggest independent evolution of multiple functional entities underlying an association locus. Pathway analyses and available expression data have already indicated promising leads for subsequent functional studies to uncover the biological significance of these findings. The IAMDGC effort has enormous potential to guide development of future drug targets and inform genetically guided management of patients.

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