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

Lars G. Fritsche; Wilmar Igl; Jessica N.Cooke Bailey; Felix Grassmann; Sebanti Sengupta; Jennifer L. Bragg-Gresham; Kathryn P. Burdon; Scott J. Hebbring; Cindy Wen; Mathias Gorski; Ivana K. Kim; David Cho; Donald Zack; Eric Souied; Hendrik P.N. Scholl; Elisa Bala; Kristine ELee; David J. Hunter; Rebecca J. Sardell; Paul Mitchell; Joanna E. Merriam; Valentina Cipriani; Joshua D. Hoffman; Tina Schick; Yara T.E. Lechanteur; Robyn H. Guymer; Matthew P. Johnson; Yingda Jiang; Chloe M. Stanton; Gabri'lle H.S. Buitendijk; Xiaowei Zhan; Alan M. Kwong; Alexis Boleda; Matthew Brooks; Linn Gieser; Rinki Ratnapriya; Kari E. Branham; Johanna R. Foerster; John R. Heckenlively; Mohammad I. Othman; Brendan J. Vote; Helena Hai Liang; Emmanuelle Souzeau; Ian L. McAllister; Timothy Isaacs; Janette Hall; Stewart Lake; David A. Mackey; Ian J. Constable; Jamie E. Craig; Terrie E. Kitchner; Zhenglin Yang; Zhiguang Su; Hongrong Luo; Daniel Chen; Hong Ouyang; Ken Flagg; Danni Lin; Guanping Mao; Henry Ferreyra; Klaus Stark; Claudia N. Von Strachwitz; Armin Wolf; Caroline Brandl; Guenther Rudolph; Matthias Olden; Margaux A. Morrison; Denise J. Morgan; Matthew Schu; Jeeyun Ahn; Giuliana Silvestri; Evangelia E. Tsironi; Kyu Hyung Park; Lindsay A. Farrer; Anton Orlin; Alexander Brucker; Mingyao Li; Christine A. Curcio; Saddek Mohand-Sa'd; José Alain Sahel; Isabelle Audo; Mustapha Benchaboune; Angela J. Cree; Christina A. Rennie; Srinivas V. Goverdhan; Michelle Grunin; Shira Hagbi-Levi; Peter Campochiaro; Nicholas Katsanis; Frank G. Holz; Frédéric Blond; Hél'ne Blanché; Jean Fran ois Deleuze; Robert P. Igo; Barbara Truitt; Neal S. Peachey; Stacy M. Meuer; Chelsea E. Myers; Emily L. Moore; Ronald Klein; Michael A. Hauser; Eric A. Postel; Monique D. Courtenay; Stephen G. Schwartz; Jaclyn L. Kovach; William K. Scott; Gerald Liew; Ava G. Tan; Bamini Gopinath; John C. Merriam; R. Theodore Smith; Jane C. Khan; Humma Shahid; Anthony T. Moore; J. Allie McGrath; Reneé Laux; Milam A. Brantley; Anita Agarwal; Lebriz Ersoy; Albert Caramoy; Thomas Langmann; Nicole T.M. Saksens; Eiko Kde Jong; Carel B. Hoyng; Melinda S. Cain; Andrea J. Richardson; Tammy M. Martin; John Blangero; Daniel E. Weeks; Bal Dhillon; Cornelia M. Van Duijn; Kimberly F. Doheny; Jane Romm; Caroline C.W. Klaver; Caroline Hayward; Michael B. Gorin; Michael L. Klein; Paul N. Baird; Anneke I. Den Hollander; Sascha Fauser; John R. WYates; Rando Allikmets; Jie Jin Wang; Debra A. Schaumberg; Barbara E.K. Klein; Stephanie A. Hagstrom; Itay Chowers; Andrew J. Lotery; Thierry Léveillard; Kang Zhang; Murray H. Brilliant; Alex W. Hewitt; Anand Swaroop; Emily Y. Chew; Margaret A. Pericak-Vance; Margaret DeAngelis; Dwight Stambolian; Jonathan L. Haines; Sudha K. Iyengar; Bernhard H.F. Weber; Gon'alo R. Abecasis; Iris M. Heid

doi:10.1038/ng.3448

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

Lars G. Fritsche, Wilmar Igl, Jessica N.Cooke Bailey, Felix Grassmann, Sebanti Sengupta, Jennifer L. Bragg-Gresham, Kathryn P. Burdon, Scott J. Hebbring, Cindy Wen, Mathias Gorski, Ivana K. Kim, David Cho, Donald Zack, Eric Souied, Hendrik P.N. Scholl, Elisa Bala, Kristine ELee, David J. Hunter, Rebecca J. Sardell, Paul MitchellJoanna E. Merriam, Valentina Cipriani, Joshua D. Hoffman, Tina Schick, Yara T.E. Lechanteur, Robyn H. Guymer, Matthew P. Johnson, Yingda Jiang, Chloe M. Stanton, Gabri'lle H.S. Buitendijk, Xiaowei Zhan, Alan M. Kwong, Alexis Boleda, Matthew Brooks, Linn Gieser, Rinki Ratnapriya, Kari E. Branham, Johanna R. Foerster, John R. Heckenlively, Mohammad I. Othman, Brendan J. Vote, Helena Hai Liang, Emmanuelle Souzeau, Ian L. McAllister, Timothy Isaacs, Janette Hall, Stewart Lake, David A. Mackey, Ian J. Constable, Jamie E. Craig, Terrie E. Kitchner, Zhenglin Yang, Zhiguang Su, Hongrong Luo, Daniel Chen, Hong Ouyang, Ken Flagg, Danni Lin, Guanping Mao, Henry Ferreyra, Klaus Stark, Claudia N. Von Strachwitz, Armin Wolf, Caroline Brandl, Guenther Rudolph, Matthias Olden, Margaux A. Morrison, Denise J. Morgan, Matthew Schu, Jeeyun Ahn, Giuliana Silvestri, Evangelia E. Tsironi, Kyu Hyung Park, Lindsay A. Farrer, Anton Orlin, Alexander Brucker, Mingyao Li, Christine A. Curcio, Saddek Mohand-Sa'd, José Alain Sahel, Isabelle Audo, Mustapha Benchaboune, Angela J. Cree, Christina A. Rennie, Srinivas V. Goverdhan, Michelle Grunin, Shira Hagbi-Levi, Peter Campochiaro, Nicholas Katsanis, Frank G. Holz, Frédéric Blond, Hél'ne Blanché, Jean Fran ois Deleuze, Robert P. Igo, Barbara Truitt, Neal S. Peachey, Stacy M. Meuer, Chelsea E. Myers, Emily L. Moore, Ronald Klein, Michael A. Hauser, Eric A. Postel, Monique D. Courtenay, Stephen G. Schwartz, Jaclyn L. Kovach, William K. Scott, Gerald Liew, Ava G. Tan, Bamini Gopinath, John C. Merriam, R. Theodore Smith, Jane C. Khan, Humma Shahid, Anthony T. Moore, J. Allie McGrath, Reneé Laux, Milam A. Brantley, Anita Agarwal, Lebriz Ersoy, Albert Caramoy, Thomas Langmann, Nicole T.M. Saksens, Eiko Kde Jong, Carel B. Hoyng, Melinda S. Cain, Andrea J. Richardson, Tammy M. Martin, John Blangero, Daniel E. Weeks, Bal Dhillon, Cornelia M. Van Duijn, Kimberly F. Doheny, Jane Romm, Caroline C.W. Klaver, Caroline Hayward, Michael B. Gorin, Michael L. Klein, Paul N. Baird, Anneke I. Den Hollander, Sascha Fauser, John R. WYates, Rando Allikmets, Jie Jin Wang, Debra A. Schaumberg, Barbara E.K. Klein, Stephanie A. Hagstrom, Itay Chowers, Andrew J. Lotery, Thierry Léveillard, Kang Zhang, Murray H. Brilliant, Alex W. Hewitt, Anand Swaroop, Emily Y. Chew, Margaret A. Pericak-Vance, Margaret DeAngelis, Dwight Stambolian, Jonathan L. Haines, Sudha K. Iyengar, Bernhard H.F. Weber, Gon'alo R. Abecasis, Iris M. Heid

Research output: Contribution to journal › Article › peer-review

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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	https://doi.org/10.1038/ng.3448
State	Published - Feb 1 2016

ASJC Scopus subject areas

Genetics

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Fritsche, L. G., Igl, W., Bailey, J. N. C., Grassmann, F., Sengupta, S., Bragg-Gresham, J. L., Burdon, K. P., Hebbring, S. J., Wen, C., Gorski, M., Kim, I. K., Cho, D., Zack, D., Souied, E., Scholl, H. P. N., Bala, E., ELee, K., Hunter, D. J., Sardell, R. J., ... Heid, I. 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. https://doi.org/10.1038/ng.3448

Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, ELee, K, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, Von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Sa'd, S, Sahel, JA, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanché, H, Deleuze, JFO, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, Van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, Den Hollander, AI, Fauser, S, WYates, JR, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Léveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR & Heid, IM 2016, 'A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants', Nature Genetics, vol. 48, no. 2, pp. 134-143. https://doi.org/10.1038/ng.3448

@article{500369b86c834eb1a1fec57c3dd67e0b,

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

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.",

author = "Fritsche, {Lars G.} and Wilmar Igl and Bailey, {Jessica N.Cooke} and Felix Grassmann and Sebanti Sengupta and Bragg-Gresham, {Jennifer L.} and Burdon, {Kathryn P.} and Hebbring, {Scott J.} and Cindy Wen and Mathias Gorski and Kim, {Ivana K.} and David Cho and Donald Zack and Eric Souied and Scholl, {Hendrik P.N.} and Elisa Bala and Kristine ELee and Hunter, {David J.} and Sardell, {Rebecca J.} and Paul Mitchell and Merriam, {Joanna E.} and Valentina Cipriani and Hoffman, {Joshua D.} and Tina Schick and Lechanteur, {Yara T.E.} and Guymer, {Robyn H.} and Johnson, {Matthew P.} and Yingda Jiang and Stanton, {Chloe M.} and Buitendijk, {Gabri'lle H.S.} and Xiaowei Zhan and Kwong, {Alan M.} and Alexis Boleda and Matthew Brooks and Linn Gieser and Rinki Ratnapriya and Branham, {Kari E.} and Foerster, {Johanna R.} and Heckenlively, {John R.} and Othman, {Mohammad I.} and Vote, {Brendan J.} and Liang, {Helena Hai} and Emmanuelle Souzeau and McAllister, {Ian L.} and Timothy Isaacs and Janette Hall and Stewart Lake and Mackey, {David A.} and Constable, {Ian J.} and Craig, {Jamie E.} and Kitchner, {Terrie E.} and Zhenglin Yang and Zhiguang Su and Hongrong Luo and Daniel Chen and Hong Ouyang and Ken Flagg and Danni Lin and Guanping Mao and Henry Ferreyra and Klaus Stark and {Von Strachwitz}, {Claudia N.} and Armin Wolf and Caroline Brandl and Guenther Rudolph and Matthias Olden and Morrison, {Margaux A.} and Morgan, {Denise J.} and Matthew Schu and Jeeyun Ahn and Giuliana Silvestri and Tsironi, {Evangelia E.} and Park, {Kyu Hyung} and Farrer, {Lindsay A.} and Anton Orlin and Alexander Brucker and Mingyao Li and Curcio, {Christine A.} and Saddek Mohand-Sa'd and Sahel, {Jos{\'e} Alain} and Isabelle Audo and Mustapha Benchaboune and Cree, {Angela J.} and Rennie, {Christina A.} and Goverdhan, {Srinivas V.} and Michelle Grunin and Shira Hagbi-Levi and Peter Campochiaro and Nicholas Katsanis and Holz, {Frank G.} and Fr{\'e}d{\'e}ric Blond and H{\'e}l'ne Blanch{\'e} and Deleuze, {Jean Fran ois} and Igo, {Robert P.} and Barbara Truitt and Peachey, {Neal S.} and Meuer, {Stacy M.} and Myers, {Chelsea E.} and Moore, {Emily L.} and Ronald Klein and Hauser, {Michael A.} and Postel, {Eric A.} and Courtenay, {Monique D.} and Schwartz, {Stephen G.} and Kovach, {Jaclyn L.} and Scott, {William K.} and Gerald Liew and Tan, {Ava G.} and Bamini Gopinath and Merriam, {John C.} and Smith, {R. Theodore} and Khan, {Jane C.} and Humma Shahid and Moore, {Anthony T.} and McGrath, {J. Allie} and Rene{\'e} Laux and Brantley, {Milam A.} and Anita Agarwal and Lebriz Ersoy and Albert Caramoy and Thomas Langmann and Saksens, {Nicole T.M.} and Jong, {Eiko Kde} and Hoyng, {Carel B.} and Cain, {Melinda S.} and Richardson, {Andrea J.} and Martin, {Tammy M.} and John Blangero and Weeks, {Daniel E.} and Bal Dhillon and {Van Duijn}, {Cornelia M.} and Doheny, {Kimberly F.} and Jane Romm and Klaver, {Caroline C.W.} and Caroline Hayward and Gorin, {Michael B.} and Klein, {Michael L.} and Baird, {Paul N.} and {Den Hollander}, {Anneke I.} and Sascha Fauser and WYates, {John R.} and Rando Allikmets and Wang, {Jie Jin} and Schaumberg, {Debra A.} and Klein, {Barbara E.K.} and Hagstrom, {Stephanie A.} and Itay Chowers and Lotery, {Andrew J.} and Thierry L{\'e}veillard and Kang Zhang and Brilliant, {Murray H.} and Hewitt, {Alex W.} and Anand Swaroop and Chew, {Emily Y.} and Pericak-Vance, {Margaret A.} and Margaret DeAngelis and Dwight Stambolian and Haines, {Jonathan L.} and Iyengar, {Sudha K.} and Weber, {Bernhard H.F.} and Abecasis, {Gon'alo R.} and Heid, {Iris M.}",

note = "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: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = feb,

day = "1",

doi = "10.1038/ng.3448",

language = "English (US)",

volume = "48",

pages = "134--143",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

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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.

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U2 - 10.1038/ng.3448

DO - 10.1038/ng.3448

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JO - Nature Genetics

JF - Nature Genetics

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ER -

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

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