title: Netrin-1 - DCC Signaling Systems and Age-Related Macular Degeneration.
abstract: We 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.
authors.affiliation: National Institute of Alcohol Abuse and Alcoholism, Section on Nutritional Neuroscience, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: John Paul
authors.initials: JP
authors.lastname: SanGiovanni
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Ankur S
authors.initials: AS
authors.lastname: Gupta
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States of America.
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC, Canada.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.affiliation: Analytic & Translational Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Phil H
authors.initials: PH
authors.lastname: Lee
mesh_terms: D000075389:DCC Receptor; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1