@article{99e3efaf92044bdd8577caa46a038be0,
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.",
author = "SanGiovanni, {John Paul} and Jing Chen and Gupta, {Ankur S.} and Smith, {Lois E.H.} and Przemyslaw Sapieha and Lee, {Phil H.}",
note = "Funding Information: PS holds a Canada Research Chair in Retinal Cell Biology and is supported by operating grants from the Canadian Institutes of Health Research (221478) and the Foundation Fighting Blindness. PHL is supported by U.S. National Institute of Mental Health (NIMH) grant K99MH101367. LEHS was supported by grants from the U.S. National Eye Institute (NEI EY022274, EY017017, PO1 HD18655), The Lowey Medical Research Institute, European Commission FP7 Project 305485 PREVENT-ROP. JPSG was supported by the NIH Intramural Research Program. JC was supported by the Bright Focus Foundation and a grant from the U.S. National Eye Institute (R01 EY024963). None of these funders had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Jing Chen is a PLOS ONE Editorial Board member. This does not alter the authors'' adherence to PLOS ONE Editorial policies and criteria. Extant GWA study findings were published by Fritsche et al.[12] The data used for the original genetic analyses were obtained from the NEI Study of Age-Related Macular Degeneration (NEI-AMD) Database found at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi? study_id = phs000182.v2.p1 (dbGaP Study Accession: phs000182.v2.p1). We thank NEI-AMD and AGC participants and the NEI-AMD and AGC Research Groups for their valuable contributions to this research project. JPSG was supported by the NIH Intramural Research Program. PS holds a Canada Research Chair in Retinal Cell Biology and is supported by operating grants from the Canadian Institutes of Health Research (221478) and the Foundation Fighting Blindness. Publisher Copyright: {\textcopyright} This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",
year = "2015",
month = may,
day = "1",
doi = "10.1371/journal.pone.0125548",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",
}