The University of Southampton
University of Southampton Institutional Repository

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

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
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 < 5 × 10(-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 = 4.1 × 10(-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.
genome-wide association studies, genomics, neurodegenerative diseases
1061-4036
134-143
Fritsche, Lars G.
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Igl, Wilmar
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Cooke Bailey, Jessica N.
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Grassmann, Felix
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Sengupta, Sebanti
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Bragg-Gresham, Jennifer L.
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Burdon, Kathryn P.
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Hebbring, Scott J.
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Wen, Cindy
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Sardell, Rebecca J.
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Mitchell, Paul
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Hoffman, Joshua D.
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Guymer, Robyn H.
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Johnson, Matthew P.
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Stanton, Chloe M.
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Buitendijk, Gabriëlle H.S.
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Brooks, Matthew
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Gieser, Linn
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McAllister, Ian L.
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Isaacs, Timothy
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von Strachwitz, Claudia N.
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Fritsche, Lars G., Igl, Wilmar, Cooke Bailey, Jessica N., Grassmann, Felix, Sengupta, Sebanti, Bragg-Gresham, Jennifer L., Burdon, Kathryn P., Hebbring, Scott J., Wen, Cindy, Gorski, Mathias, Kim, Ivana K., Cho, David, Zack, Donald, Souied, Eric, Scholl, Hendrik P.N., Bala, Elisa, Lee, Kristine E., Hunter, David J., Sardell, Rebecca J., Mitchell, Paul, Merriam, Joanna E., Cipriani, Valentina, Hoffman, Joshua D., Schick, Tina, Lechanteur, Yara T.E., Guymer, Robyn H., Johnson, Matthew P., Jiang, Yingda, Stanton, Chloe M., Buitendijk, Gabriëlle H.S., Zhan, Xiaowei, Kwong, Alan M., Boleda, Alexis, Brooks, Matthew, Gieser, Linn, Ratnapriya, Rinki, Branham, Kari E., Foerster, Johanna R., Heckenlively, John R., Othman, Mohammad I., Vote, Brendan J., Liang, Helena Hai, Souzeau, Emmanuelle, McAllister, Ian L., Isaacs, Timothy, Hall, Janette, Lake, Stewart, Mackey, David A., Constable, Ian J., Craig, Jamie E., Kitchner, Terrie E., Yang, Zhenglin, Su, Zhiguang, Luo, Hongrong, Chen, Daniel, Ouyang, Hong, Flagg, Ken, Lin, Danni, Mao, Guanping, Ferreyra, Henry, Stark, Klaus, von Strachwitz, Claudia N., Wolf, Armin, Brandl, Caroline, Rudolph, Guenther, Olden, Matthias, Morrison, Margaux A., Morgan, Denise J, Schu, Matthew, Ahn, Jeeyun, Silvestri, Giuliana, Tsironi, Evangelia E., Park, Kyu Hyung, Farrer, Lindsay A., Orlin, Anton, Brucker, Alexander, Li, Mingyao, Curcio, Christine A., Mohand-Saïd, Saddek, Sahel, José-Alain, Audo, Isabelle, Benchaboune, Mustapha, Cree, Angela J., Rennie, Christina A., Goverdhan, Srinivas V., Grunin, Michelle, Hagbi-Levi, Shira, Campochiaro, Peter, Katsanis, Nicholas, Holz, Frank G., Blond, Frédéric, Blanché, Hélène, Deleuze, Jean-François, Igo, Robert P., Truitt, Barbara, Peachey, Neal S., Meuer, Stacy M., Myers, Chelsea E., Moore, Emily L., Klein, Ronald, Hauser, Michael A., Postel, Eric A., Courtenay, Monique D., Schwartz, Stephen G., Kovach, Jaclyn L., Scott, William K., Liew, Gerald, Tan, Ava G., Gopinath, Bamini, Merriam, John C., Smith, R. Theodore, Khan, Jane C., Shahid, Humma, Moore, Anthony T., McGrath, J. Allie, Laux, Reneé, Brantley, Milam A., Agarwal, Anita, Ersoy, Lebriz, Caramoy, Albert, Langmann, Thomas, Saksens, Nicole T.M., de Jong, Eiko K., Hoyng, Carel B., Cain, Melinda S., Richardson, Andrea J., Martin, Tammy M., Blangero, John, Weeks, Daniel E., Dhillon, Bal, van Duijn, Cornelia M., Doheny, Kimberly F., Romm, Jane, Klaver, Caroline C.W., Hayward, Caroline, Gorin, Michael B., Klein, Michael L., Baird, Paul N., den Hollander, Anneke I., Fauser, Sascha, Yates, John R.W., Allikmets, Rando, Wang, Jie Jin, Schaumberg, Debra A., Klein, Barbara E.K., Hagstrom, Stephanie A., Chowers, Itay, Lotery, Andrew J., Léveillard, Thierry, Zhang, Kang, Brilliant, Murray H., Hewitt, Alex W., Swaroop, Anand, Chew, Emily Y., Pericak-Vance, Margaret A., DeAngelis, Margaret, Stambolian, Dwight, Haines, Jonathan L., Iyengar, Sudha K., Weber, Bernhard H.F., Abecasis, Gonçalo R. and Heid, Iris M. (2016) A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nature Genetics, 48 (2), 134-143. (doi:10.1038/ng.3448). (PMID:26691988)

Record type: Article

Abstract

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 < 5 × 10(-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 = 4.1 × 10(-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.

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More information

Accepted/In Press date: 22 October 2015
e-pub ahead of print date: 21 December 2015
Published date: February 2016
Keywords: genome-wide association studies, genomics, neurodegenerative diseases
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 386795
URI: http://eprints.soton.ac.uk/id/eprint/386795
ISSN: 1061-4036
PURE UUID: d5ab8d24-672a-4165-be31-992aef1ecf03
ORCID for Angela J. Cree: ORCID iD orcid.org/0000-0002-1987-8900
ORCID for Andrew J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305

Catalogue record

Date deposited: 04 Feb 2016 14:22
Last modified: 15 Mar 2024 03:24

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Contributors

Author: Lars G. Fritsche
Author: Wilmar Igl
Author: Jessica N. Cooke Bailey
Author: Felix Grassmann
Author: Sebanti Sengupta
Author: Jennifer L. Bragg-Gresham
Author: Kathryn P. Burdon
Author: Scott J. Hebbring
Author: Cindy Wen
Author: Mathias Gorski
Author: Ivana K. Kim
Author: David Cho
Author: Donald Zack
Author: Eric Souied
Author: Hendrik P.N. Scholl
Author: Elisa Bala
Author: Kristine E. Lee
Author: David J. Hunter
Author: Rebecca J. Sardell
Author: Paul Mitchell
Author: Joanna E. Merriam
Author: Valentina Cipriani
Author: Joshua D. Hoffman
Author: Tina Schick
Author: Yara T.E. Lechanteur
Author: Robyn H. Guymer
Author: Matthew P. Johnson
Author: Yingda Jiang
Author: Chloe M. Stanton
Author: Gabriëlle H.S. Buitendijk
Author: Xiaowei Zhan
Author: Alan M. Kwong
Author: Alexis Boleda
Author: Matthew Brooks
Author: Linn Gieser
Author: Rinki Ratnapriya
Author: Kari E. Branham
Author: Johanna R. Foerster
Author: John R. Heckenlively
Author: Mohammad I. Othman
Author: Brendan J. Vote
Author: Helena Hai Liang
Author: Emmanuelle Souzeau
Author: Ian L. McAllister
Author: Timothy Isaacs
Author: Janette Hall
Author: Stewart Lake
Author: David A. Mackey
Author: Ian J. Constable
Author: Jamie E. Craig
Author: Terrie E. Kitchner
Author: Zhenglin Yang
Author: Zhiguang Su
Author: Hongrong Luo
Author: Daniel Chen
Author: Hong Ouyang
Author: Ken Flagg
Author: Danni Lin
Author: Guanping Mao
Author: Henry Ferreyra
Author: Klaus Stark
Author: Claudia N. von Strachwitz
Author: Armin Wolf
Author: Caroline Brandl
Author: Guenther Rudolph
Author: Matthias Olden
Author: Margaux A. Morrison
Author: Denise J Morgan
Author: Matthew Schu
Author: Jeeyun Ahn
Author: Giuliana Silvestri
Author: Evangelia E. Tsironi
Author: Kyu Hyung Park
Author: Lindsay A. Farrer
Author: Anton Orlin
Author: Alexander Brucker
Author: Mingyao Li
Author: Christine A. Curcio
Author: Saddek Mohand-Saïd
Author: José-Alain Sahel
Author: Isabelle Audo
Author: Mustapha Benchaboune
Author: Angela J. Cree ORCID iD
Author: Christina A. Rennie
Author: Srinivas V. Goverdhan
Author: Michelle Grunin
Author: Shira Hagbi-Levi
Author: Peter Campochiaro
Author: Nicholas Katsanis
Author: Frank G. Holz
Author: Frédéric Blond
Author: Hélène Blanché
Author: Jean-François Deleuze
Author: Robert P. Igo
Author: Barbara Truitt
Author: Neal S. Peachey
Author: Stacy M. Meuer
Author: Chelsea E. Myers
Author: Emily L. Moore
Author: Ronald Klein
Author: Michael A. Hauser
Author: Eric A. Postel
Author: Monique D. Courtenay
Author: Stephen G. Schwartz
Author: Jaclyn L. Kovach
Author: William K. Scott
Author: Gerald Liew
Author: Ava G. Tan
Author: Bamini Gopinath
Author: John C. Merriam
Author: R. Theodore Smith
Author: Jane C. Khan
Author: Humma Shahid
Author: Anthony T. Moore
Author: J. Allie McGrath
Author: Reneé Laux
Author: Milam A. Brantley
Author: Anita Agarwal
Author: Lebriz Ersoy
Author: Albert Caramoy
Author: Thomas Langmann
Author: Nicole T.M. Saksens
Author: Eiko K. de Jong
Author: Carel B. Hoyng
Author: Melinda S. Cain
Author: Andrea J. Richardson
Author: Tammy M. Martin
Author: John Blangero
Author: Daniel E. Weeks
Author: Bal Dhillon
Author: Cornelia M. van Duijn
Author: Kimberly F. Doheny
Author: Jane Romm
Author: Caroline C.W. Klaver
Author: Caroline Hayward
Author: Michael B. Gorin
Author: Michael L. Klein
Author: Paul N. Baird
Author: Anneke I. den Hollander
Author: Sascha Fauser
Author: John R.W. Yates
Author: Rando Allikmets
Author: Jie Jin Wang
Author: Debra A. Schaumberg
Author: Barbara E.K. Klein
Author: Stephanie A. Hagstrom
Author: Itay Chowers
Author: Thierry Léveillard
Author: Kang Zhang
Author: Murray H. Brilliant
Author: Alex W. Hewitt
Author: Anand Swaroop
Author: Emily Y. Chew
Author: Margaret A. Pericak-Vance
Author: Margaret DeAngelis
Author: Dwight Stambolian
Author: Jonathan L. Haines
Author: Sudha K. Iyengar
Author: Bernhard H.F. Weber
Author: Gonçalo R. Abecasis
Author: Iris M. Heid

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