PT - JOURNAL ARTICLE AU - Erin K. Wagner AU - Yi Yu AU - Eric H. Souied AU - Ilkka J. Immonen AU - Soumya Raychaudhuri AU - Mark J. Daly AU - Johanna M. Seddon TI - Novel protective associations with age-related macular degeneration: A common variant near <em>CTRB1</em> and a rare variant in <em>PELI3</em> AID - 10.1101/034173 DP - 2015 Jan 01 TA - bioRxiv PG - 034173 4099 - http://biorxiv.org/content/early/2015/12/11/034173.short 4100 - http://biorxiv.org/content/early/2015/12/11/034173.full AB - Although &gt;20 common frequency age-related macular degeneration (AMD) alleles have been discovered with genome-wide association studies, substantial disease heritability remains unexplained. In this study we sought to identify additional variants, both common and rare, that have an association with advanced AMD. We genotyped 4,332 cases and 4,642 controls of European ancestry from three different populations using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants and performed single variant and gene-based burden tests to identify associations with rare variants. We identified a novel rare (minor allele frequency &lt; 1%) non-synonymous variant; A307V in the PELI3 gene (odds ratio [OR]=0.27, P=5.6×10−7). Additionally we identified an enrichment of protective alleles in PELI3 using a burden test (OR=0.28). The new rare variant has a large effect size, similar to rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR=18.82, P=3.5×10−07), CFHN1050Y (OR=0.40, P=8.0×10−13), C3K155Q (OR=3.27, P=1.5×10−10), and C9P167S (OR=2.04, P=2.8×10−07). We also identified a novel common variant (rs8056814) near CTRB1 significantly associated with a decrease in AMD risk (odds ratio=0.71, P=7.7×10−07). This study supports the involvement of both common and rare protective variants in AMD. It also may expand the role of the high-density lipoprotein pathway and branches of the innate immune pathway, outside that of the complement system, in the etiology of AMD.