SanGiovanni, John PaulChen, JingGupta, Ankur S.Smith, LoisSapieha, PrzemyslawLee, Phil2015-06-022015SanGiovanni, John Paul, Jing Chen, Ankur S. Gupta, Lois E. H. Smith, Przemyslaw Sapieha, and Phil H. Lee. 2015. “Netrin-1 – DCC Signaling Systems and Age-Related Macular Degeneration.” PLoS ONE 10 (5): e0125548. doi:10.1371/journal.pone.0125548. http://dx.doi.org/10.1371/journal.pone.0125548.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:16121032We conducted a nested candidate gene study and pathway-based enrichment analysis on data from a multi-national 77,000-person project on the molecular genetics of age-related macular degeneration (AMD) to identify AMD-associated DNA-sequence variants in genes encoding constituents of a netrin-1 (NTN1)-based signaling pathway that converges on DNA-binding transcription complexes through a 3'-5'-cyclic adenosine monophosphate-calcineurin (cAMP-CN)-dependent axis. AMD-associated single nucleotide polymorphisms (SNPs) existed in 9 linkage disequilibrium-independent genomic regions; these included loci overlapping NTN1 (rs9899630, P ≤ 9.48 x 10-5), DCC (Deleted in Colorectal Cancer)—the gene encoding a primary NTN1 receptor (rs8097127, P ≤ 3.03 x 10-5), and 6 other netrin-related genes. Analysis of the NTN1-DCC pathway with exact methods demonstrated robust enrichment with AMD-associated SNPs (corrected P-value = 0.038), supporting the idea that processes driven by NTN1-DCC signaling systems operate in advanced AMD. The NTN1-DCC pathway contains targets of FDA-approved drugs and may offer promise for guiding applied clinical research on preventive and therapeutic interventions for AMD.en-USJournal Article2015-06-0210.1371/journal.pone.0125548