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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 134-143 |
| Number of pages | 10 |
| Journal | Nature Genetics |
| Volume | 48 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2016 |
ASJC Scopus subject areas
- Genetics
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A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. / Fritsche, Lars G.; Igl, Wilmar; Bailey, Jessica N.Cooke; 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; ELee, Kristine; 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, Gabri'lle 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-Sa'd, 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, Hél'ne; Deleuze, Jean Fran ois; 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.; Jong, Eiko Kde; 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; WYates, John R.; 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, Gon'alo R.; Heid, Iris M.
In: Nature Genetics, Vol. 48, No. 2, 01.02.2016, p. 134-143.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
AU - Fritsche, Lars G.
AU - Igl, Wilmar
AU - Bailey, Jessica N.Cooke
AU - Grassmann, Felix
AU - Sengupta, Sebanti
AU - Bragg-Gresham, Jennifer L.
AU - Burdon, Kathryn P.
AU - Hebbring, Scott J.
AU - Wen, Cindy
AU - Gorski, Mathias
AU - Kim, Ivana K.
AU - Cho, David
AU - Zack, Donald
AU - Souied, Eric
AU - Scholl, Hendrik P.N.
AU - Bala, Elisa
AU - ELee, Kristine
AU - Hunter, David J.
AU - Sardell, Rebecca J.
AU - Mitchell, Paul
AU - Merriam, Joanna E.
AU - Cipriani, Valentina
AU - Hoffman, Joshua D.
AU - Schick, Tina
AU - Lechanteur, Yara T.E.
AU - Guymer, Robyn H.
AU - Johnson, Matthew P.
AU - Jiang, Yingda
AU - Stanton, Chloe M.
AU - Buitendijk, Gabri'lle H.S.
AU - Zhan, Xiaowei
AU - Kwong, Alan M.
AU - Boleda, Alexis
AU - Brooks, Matthew
AU - Gieser, Linn
AU - Ratnapriya, Rinki
AU - Branham, Kari E.
AU - Foerster, Johanna R.
AU - Heckenlively, John R.
AU - Othman, Mohammad I.
AU - Vote, Brendan J.
AU - Liang, Helena Hai
AU - Souzeau, Emmanuelle
AU - McAllister, Ian L.
AU - Isaacs, Timothy
AU - Hall, Janette
AU - Lake, Stewart
AU - Mackey, David A.
AU - Constable, Ian J.
AU - Craig, Jamie E.
AU - Kitchner, Terrie E.
AU - Yang, Zhenglin
AU - Su, Zhiguang
AU - Luo, Hongrong
AU - Chen, Daniel
AU - Ouyang, Hong
AU - Flagg, Ken
AU - Lin, Danni
AU - Mao, Guanping
AU - Ferreyra, Henry
AU - Stark, Klaus
AU - Von Strachwitz, Claudia N.
AU - Wolf, Armin
AU - Brandl, Caroline
AU - Rudolph, Guenther
AU - Olden, Matthias
AU - Morrison, Margaux A.
AU - Morgan, Denise J.
AU - Schu, Matthew
AU - Ahn, Jeeyun
AU - Silvestri, Giuliana
AU - Tsironi, Evangelia E.
AU - Park, Kyu Hyung
AU - Farrer, Lindsay A.
AU - Orlin, Anton
AU - Brucker, Alexander
AU - Li, Mingyao
AU - Curcio, Christine A.
AU - Mohand-Sa'd, Saddek
AU - Sahel, José Alain
AU - Audo, Isabelle
AU - Benchaboune, Mustapha
AU - Cree, Angela J.
AU - Rennie, Christina A.
AU - Goverdhan, Srinivas V.
AU - Grunin, Michelle
AU - Hagbi-Levi, Shira
AU - Campochiaro, Peter
AU - Katsanis, Nicholas
AU - Holz, Frank G.
AU - Blond, Frédéric
AU - Blanché, Hél'ne
AU - Deleuze, Jean Fran ois
AU - Igo, Robert P.
AU - Truitt, Barbara
AU - Peachey, Neal S.
AU - Meuer, Stacy M.
AU - Myers, Chelsea E.
AU - Moore, Emily L.
AU - Klein, Ronald
AU - Hauser, Michael A.
AU - Postel, Eric A.
AU - Courtenay, Monique D.
AU - Schwartz, Stephen G.
AU - Kovach, Jaclyn L.
AU - Scott, William K.
AU - Liew, Gerald
AU - Tan, Ava G.
AU - Gopinath, Bamini
AU - Merriam, John C.
AU - Smith, R. Theodore
AU - Khan, Jane C.
AU - Shahid, Humma
AU - Moore, Anthony T.
AU - McGrath, J. Allie
AU - Laux, Reneé
AU - Brantley, Milam A.
AU - Agarwal, Anita
AU - Ersoy, Lebriz
AU - Caramoy, Albert
AU - Langmann, Thomas
AU - Saksens, Nicole T.M.
AU - Jong, Eiko Kde
AU - Hoyng, Carel B.
AU - Cain, Melinda S.
AU - Richardson, Andrea J.
AU - Martin, Tammy M.
AU - Blangero, John
AU - Weeks, Daniel E.
AU - Dhillon, Bal
AU - Van Duijn, Cornelia M.
AU - Doheny, Kimberly F.
AU - Romm, Jane
AU - Klaver, Caroline C.W.
AU - Hayward, Caroline
AU - Gorin, Michael B.
AU - Klein, Michael L.
AU - Baird, Paul N.
AU - Den Hollander, Anneke I.
AU - Fauser, Sascha
AU - WYates, John R.
AU - Allikmets, Rando
AU - Wang, Jie Jin
AU - Schaumberg, Debra A.
AU - Klein, Barbara E.K.
AU - Hagstrom, Stephanie A.
AU - Chowers, Itay
AU - Lotery, Andrew J.
AU - Léveillard, Thierry
AU - Zhang, Kang
AU - Brilliant, Murray H.
AU - Hewitt, Alex W.
AU - Swaroop, Anand
AU - Chew, Emily Y.
AU - Pericak-Vance, Margaret A.
AU - DeAngelis, Margaret
AU - Stambolian, Dwight
AU - Haines, Jonathan L.
AU - Iyengar, Sudha K.
AU - Weber, Bernhard H.F.
AU - Abecasis, Gon'alo R.
AU - Heid, Iris M.
N1 - Funding Information: We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H. The authors declare competing financial interests: details are available in the online version of the paper. Publisher Copyright: © 2016 Nature America, Inc.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84981164833&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84981164833&partnerID=8YFLogxK
U2 - 10.1038/ng.3448
DO - 10.1038/ng.3448
M3 - Article
C2 - 26691988
AN - SCOPUS:84981164833
VL - 48
SP - 134
EP - 143
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 2
ER -