dbGaP phs001046 Genomic Architecture of Progression and Treatment Response in AMD

*Whole exome sequencing*: 3 sets of phenotypically extreme individuals of European ancestry were whole exome sequenced. *1. Risk extremes* To target novel AMD risk and protective variants we sequenced 99 phenotypically extreme individuals; 49 cases and 50 controls. Inclusion/exclusion criteria: *Extreme cases* *Inclusion*: individuals with bilateral advanced choroidal neovascular (AREDS grade 5) AMD. *Extreme controls* *Inclusion*: unaffected controls (bilateral AREDS grade 1) with no (or very few) small drusen. *2. Progression extremes* To target variants associated with progression of AMD we whole exome sequenced 35 individuals that progressed quickly to advanced AMD (fast-progressors) and 30 individuals that did not progress quickly (maintainers): Inclusion/exclusion criteria: *Fast-progressors* *Inclusion*: individuals with at least 1 eye that progressed from AREDS grade 2, 3 or 4 to grade 5 in a year or less. *Maintainers* *Inclusion*: individuals with at least 1 eye that remained at grade 3 for at least 4 years. *3. Treatment response* To target variants associated with the response to anti-angiogenesis treatment of advanced neovascular AMD (AREDS grade 5), we whole exome sequenced 43 grade 5 individuals with a baseline exam and a follow-up exam at one year. Treatment response was defined using gain/loss of lines of vision, change in intraretinal or subretinal fluid and central retinal thickness. Treatment response was characterized qualitatively as: *1. GOOD RESPONSE* - three lines of vision gain, prolonged or persistent (at least 6 months) absence of SRF on OCT, absence of intraretinal fluid on OCT, presence of unchanged small intraretinal cysts with no recurrence of SRF; *2. PARTIAL RESPONSE* - decrease in SRF and intraretinal fluid, but not complete absence; *3. RESPONSE WITH RECURRENCE* - Recurrence of SRF and or intraretinal fluid after good response for at least 6 months; *4. POOR RESPONSE* - three lines of vision loss, persistent SRF and IRF, formation of disciform scar. *Inclusion/exclusion criteria*: *Inclusion*: Individuals with at least one follow-up exam one year (7-17 months) after baseline exam were included. *Exome-chip genotyping*: We exome-chip genotyped all individuals ascertained for this study that had not been genotyped at CIDR by the International AMD Genomics Consortium. These were done on 2 Illumina chips, 384 on the first and 356 on the second, 740 in total. We have 627 cases and 56 controls. We will provide updated phenotype files for the exome chip genotyped individuals as we continue in our analyses.