title: Set-based joint test of interaction between SNPs in the VEGF pathway and exogenous estrogen finds association with age-related macular degeneration.
abstract: Purpose:Age-Related Macular Degeneration (AMD) is the leading cause of irreversible visual loss in developed countries. Its etiology includes genetic and environmental factors. Although VEGFA variants are associated with AMD, the joint action of variants within the VEGF pathway and their interaction with non-genetic factors has not been investigated. Methods:Affymetrix 6.0 chipsets were used to genotype 668,238 SNPs in 1,207 AMD cases and 686 controls. Environmental exposures were collected by questionnaire. A set-based test was conducted using the chi-square statistic at each SNP derived from Kraft's 2df joint test. Pathway and gene-based test statistics were calculated as the mean of all independent SNP statistics. Phenotype labels were permuted 10,000 times to generate an empirical p-value. Results: While a main effect of the VEGF pathway was not identified, the pathway was associated with neovascular AMD in women when accounting for birth control pill (BCP) use (P= 0.017). Analysis of VEGF's subpathways found that SNPs in the Proliferation subpathway were associated with neovascular AMD (P=0.029) when accounting for BCP use. Nominally significant genes within this subpathway were also observed. Stratification by BCP use revealed novel significant genetic effects in women who had taken BCPs. Conclusions: These results illustrate that some AMD genetic risk factors may only be revealed when considering complex relationships among risk factors. This shows the utility of exploring pathways of previously associated genes to find novel effects. It also demonstrates the importance of incorporating environmental exposures in tests of genetic association at the SNP, gene, or pathway level.
authors.affiliation: Human Genetics and Genomics, University of Miami Miller School Medicine, 1501 NW 10th Ave, Miami, FL, 33136, United States.
authors.forename: Monique D
authors.initials: MD
authors.lastname: Courtenay
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, BRB-314 (M860), Miami, Florida, 33136, United States.
authors.forename: William
authors.initials: W
authors.lastname: Cade
authors.affiliation: Ophthalmology, Bascom Palmer Eye Institute, Retina Center of Naples, 311 9th Street North, Naples, Florida, 34102, United States of America.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Schwartz
authors.affiliation: Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 311 9th St N, Naples, FL, 34102, United States of America.
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Kovach
authors.affiliation: VEI, Vanderbilt University, 2311 Pierce avenue, Nashville, Tennessee, 37232-8808, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue; BRB 525, Miami, Florida, 33136, United States.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Epidemiology & Biostatistics, Case Western Reserve University, 2-529 Wolstein Research Building, 2103 Cornell Road, Cleveland, Ohio, 44106, United States.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, BRB-314 (M860), Miami, Florida, 33136, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave., Biomedical Research Building (BRB) # 414, Miami, Florida, 33136, United States w.scott@med.miami.edu.
authors.forename: Wiliam K
authors.initials: WK
authors.lastname: Scott