TY - JOUR
T1 - Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration
AU - Yu, Yi
AU - Bhangale, Tushar R.
AU - Fagerness, Jesen
AU - Ripke, Stephan
AU - Thorleifsson, Gudmar
AU - Tan, Perciliz L.
AU - Souied, Eric H.
AU - Richardson, Andrea J.
AU - Merriam, Joanna E.
AU - Buitendijk, Gabriëlle H.S.
AU - Reynolds, Robyn
AU - Raychaudhuri, Soumya
AU - Chin, Kimberly A.
AU - Sobrin, Lucia
AU - Evangelou, Evangelos
AU - Lee, Phil H.
AU - Lee, Aaron Y.
AU - Leveziel, Nicolas
AU - Zack, Donald J.
AU - Campochiaro, Betsy
AU - Campochiaro, Peter
AU - Smith, R. Theodore
AU - Barile, Gaetano R.
AU - Guymer, Robyn H.
AU - Hogg, Ruth
AU - Chakravarthy, Usha
AU - Robman, Luba D.
AU - Gustafsson, Omar
AU - Sigurdsson, Haraldur
AU - Ortmann, Ward
AU - Behrens, Timothy W.
AU - Stefansson, Kari
AU - Uitterlinden, André G.
AU - van Duijn, Cornelia M.
AU - Vingerling, Johannes R.
AU - Klaver, Caroline C.W.
AU - Allikmets, Rando
AU - Brantley, Milam A.
AU - Baird, Paul N.
AU - Katsanis, Nicholas
AU - Thorsteinsdottir, Unnur
AU - Ioannidis, John P.A.
AU - Daly, Mark J.
AU - Graham, Robert R.
AU - Seddon, Johanna M.
N1 - Funding Information:
We deeply appreciate the support of a generous anonymous donor to the research of J.M.S., without whom the Tufts/ MGH genome-wide association study would not have been possible. This research was also supported in part by grants RO1-EY11309, RO1-EY13435, R24-EY017404, P30-EY 001765 and K12-EY16335 from the National Institutes of Health, Bethesda, MD, USA; Massachusetts Lions Eye Research Fund, Inc.; Unrestricted grants and Career Development Award from Research to Prevent Blindness, Inc., New York, NY, USA; Foundation Fighting Blindness, Owing Mills, MD, USA; The Macula Vision Research Foundation; Kaplen Foundation; Widgeon Point Charitable Foundation; the Alcon Research Institute; a Fight for Sight postdoctoral award; the National Health and Medical Research Council of Australia Centre for Clinical Research Excellence No. 529923—Translational Clinical Research in Major Eye Diseases and a Practitioner Fellowship to R.H.G. and Operational Infrastructure Support from the Victorian Government; American Macular Degeneration Foundation; and the Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA. Funding to pay the Open Access publication charges for this article was provided by the Macular Degeneration Research Fund, Tufts Medical Center.
Funding Information:
We thank the participants, their families and numerous ophthalmologists throughout the country who participated in this study, the MIGen study group and the Brigham and Women’s Hospital PhenoGenetic Project for providing DNA samples that were used in this study, the AREDS Research Group, and Dr J. Barre, Dr. J.C. Danan and P. Ledudal from the Clinical Researches Functional Unit, CHI Creteil, France. The MMAP dataset used for the analyses described in this manuscript was obtained from the NEI Study of Age-Related Macular Degeneration (NEI-AMD) Database found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000182.v2.p1. Funding support for NEI-AMD was provided by the National Eye Institute. We would like to thank NEI-AMD participants and the NEI-AMD Research Group for their valuable contribution to this research. Funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The datasets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL, USA).
PY - 2011/9
Y1 - 2011/9
N2 - Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P 5 1.1 × 10-8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P 5 8.7 × 10-9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genomewide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
AB - Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P 5 1.1 × 10-8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P 5 8.7 × 10-9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genomewide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
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U2 - 10.1093/hmg/ddr270
DO - 10.1093/hmg/ddr270
M3 - Article
C2 - 21665990
AN - SCOPUS:80052196120
SN - 0964-6906
VL - 20
SP - 3699
EP - 3709
JO - Human molecular genetics
JF - Human molecular genetics
IS - 18
M1 - ddr270
ER -