eCite Digital Repository

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants


Fritsche, LG and Igl, W and Bailey, JN and Grassmann, F and Sengupta, S and Bragg-Gresham, JL and Burdon, KP and Hebbring, SJ and Wen, C and Gorski, M and Kim, IK and Cho, D and Zack, D and Souied, E and Scholl, HPN and Bala, E and Lee, KE and Hunter, DJ and Sardell, RJ and Mitchell, P and Merriam, JE and Cipriani, V and Hoffman, JD and Schick, T and Lechanteur, YTE and Guymer, RH and Johnson, MP and Jiang, Y and Stanton, CM and Buitendijk, GH and Zhan, X and Kwong, AM and Boleda, A and Brooks, M and Gieser, L and Ratnapriya, R and Branham, KE and Foerster, JR and Heckenlively, JR and Othman, MI and Vote, BJ and Liang, HH and Souzeau, E and McAllister, IL and Isaacs, T and Hall, J and Lake, S and Mackey, DA and Constable, IJ and Craig, JE and Kitchner, TE and Yang, Z and Su, Z and Luo, H and Chen, D and Ouyang, H and Flagg, K and Lin, D and Mao, G and Ferreyra, H and Stark, K and von Strachwitz, CN and Wolf, A and Brandl, C and Rudolph, G and Olden, M and Morrison, MA and Morgan, DJ and Schu, M and Ahn, J and Silvestri, G and Tsironi, EE and Park, KH and Farrer, LA and Orlin, A and Brucker, A and Li, M and Curcio, CA and Mohand-Said, S and Sahel, J-A and Audo, I and Benchaboune, M and Cree, AJ and Rennie, CA and Goverdhan, SV and Grunin, M and Hagbi-Levi, S and Campochiaro, P and Katsanis, N and Holz, FG and Blond, F and Blanche, H and Deleuze, J-F and Igo Jr, RP and Truitt, B and Peachey, NS and Meuer, SM and Myers, CE and Moore, EL and Klein, R and Hauser, MA and Postel, EA and Courtenay, MD and Schwartz, SG and Kovach, JL and Scott, WK and Liew, G and Tan, AG and Gopinath, B and Merriam, JC and Smith, RT and Khan, JC and Shahid, H and Moore, AT and McGrath, JA and Laux, R and Brantley Jr, MA and Agarwal, A and Ersoy, L and Caramoy, A and Langmann, T and Saksens, NTM and de Jong, EK and Hoyng, CB and Cain, MS and Richardson, AJ and Martin, TM and Blangero, J and Weeks, DE and Dhillon, B and van Duijn, CM and Doheny, KF and Romm, J and Klaver, CC and Hayward, C and Gorin, MB and Klein, ML and Baird, PN and den Hollander, AI and Fauser, S and Yates, JRW and Allikmets, R and Wang, JJ and Schaumberg, DA and Klein, BEK and Hagstrom, SA and Chowers, I and Lotery, AJ and Leveillard, T and Zhang, K and Brilliant, MH and Hewitt, AW and Swaroop, A and Chew, EY and Pericak-Vance, MA and DeAngelis, M and Stambolian, D and Haines, JL and Iyengar, SK and Weber, BH and Abecasis, GR and Heid, IM, A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants, Nature Genetics, 48, (2) pp. 134-143. ISSN 1546-1718 (2015) [Refereed Article]

Copyright Statement

2016 Nature America

DOI: doi:10.1038/ng.3448


Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P<5נ10−8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value =4.1נ10−10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Item Details

Item Type:Refereed Article
Keywords:genome-wide association studies, genomics, neurodegenerative diseases
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
UTAS Author:Vote, BJ (Dr Brendan Vote)
UTAS Author:Mackey, DA (Professor David Mackey)
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:105915
Year Published:2015
Web of Science® Times Cited:758
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-01-20
Last Modified:2017-11-06

Repository Staff Only: item control page