International AMD Genomics Consortium - Exome Chip Experiment

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. To further our understanding of AMD genetics, we examined the contribution of common and rare genetic variation in the International AMD Genomics Consortium that included ~50,000 samples of 26 AMD case - control cohorts that were jointly genotyped. Analyzing 16,144 patients with late stage AMD and 17,832 controls, we identified 52 independently associated common and rare variants distributed across 34 loci. Besides these single variant signals, we also observed gene-based enrichment of very rare coding variants (frequency < 0.1%) in cases that implicated causal roles for CFH, CFI and TIMP3 in three of the known AMD risk loci. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.]]>
Inclusion criteria: Cases: Avanced AMD cases with GA and/or CNV in at least one eye and age at first diagnosis >= 50 years, intermediate AMD cases with pigmentary changes in the RPE or more than five macular drusen greater than 63μm and age at first diagnosis >= 50 years. Controls: Without known advanced or intermediate AMD. Recruitment and ascertainment strategies varied by study. Exclusion criteria (cases and controls): Duplicated and related individuals (kinship coefficient Φ >= 0.0884, i.e. 3rd degree relatives or closer) Subjects with discrepancies between reported gender and sex chromosomal information or with atypical sex chromosome configurations Subjects with genotyping call rates < 98.5% ]]>