Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

Xiaowei Zhan; David E. Larson; Chaolong Wang; Daniel C. Koboldt; Yuri V. Sergeev; Robert S. Fulton; Lucinda L. Fulton; Catrina C. Fronick; Kari E. Branham; Jennifer Bragg-Gresham; Goo Jun; Youna Hu; Hyun Min Kang; Dajiang Liu; Mohammad Othman; Matthew Brooks; Rinki Ratnapriya; Alexis Boleda; Felix Grassmann; Claudia Von Strachwitz; Lana M. Olson; Gabriëlle H.S. Buitendijk; Albert Hofman; Cornelia M. Van Duijn; Valentina Cipriani; Anthony T. Moore; Humma Shahid; Yingda Jiang; Yvette P. Conley; Denise J. Morgan; Ivana K. Kim; Matthew P. Johnson; Stuart Cantsilieris; Andrea J. Richardson; Robyn H. Guymer; Hongrong Luo; Hong Ouyang; Christoph Licht; Fred G. Pluthero; Mindy M. Zhang; Kang Zhang; Paul N. Baird; John Blangero; Michael L. Klein; Lindsay A. Farrer; Margaret M. DeAngelis; Daniel E. Weeks; Michael B. Gorin; John R.W. Yates; Caroline C.W. Klaver; Margaret A. Pericak-Vance; Jonathan L. Haines; Bernhard H.F. Weber; Richard K. Wilson; John R. Heckenlively; Emily Y. Chew; Dwight Stambolian; Elaine R. Mardis; Anand Swaroop; Goncalo R. Abecasis

doi:10.1038/ng.2758

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

Xiaowei Zhan, David E. Larson, Chaolong Wang, Daniel C. Koboldt, Yuri V. Sergeev, Robert S. Fulton, Lucinda L. Fulton, Catrina C. Fronick, Kari E. Branham, Jennifer Bragg-Gresham, Goo Jun, Youna Hu, Hyun Min Kang, Dajiang Liu, Mohammad Othman, Matthew Brooks, Rinki Ratnapriya, Alexis Boleda, Felix Grassmann, Claudia Von StrachwitzLana M. Olson, Gabriëlle H.S. Buitendijk, Albert Hofman, Cornelia M. Van Duijn, Valentina Cipriani, Anthony T. Moore, Humma Shahid, Yingda Jiang, Yvette P. Conley, Denise J. Morgan, Ivana K. Kim, Matthew P. Johnson, Stuart Cantsilieris, Andrea J. Richardson, Robyn H. Guymer, Hongrong Luo, Hong Ouyang, Christoph Licht, Fred G. Pluthero, Mindy M. Zhang, Kang Zhang, Paul N. Baird, John Blangero, Michael L. Klein, Lindsay A. Farrer, Margaret M. DeAngelis, Daniel E. Weeks, Michael B. Gorin, John R.W. Yates, Caroline C.W. Klaver, Margaret A. Pericak-Vance, Jonathan L. Haines, Bernhard H.F. Weber, Richard K. Wilson, John R. Heckenlively, Emily Y. Chew, Dwight Stambolian, Elaine R. Mardis, Anand Swaroop, Goncalo R. Abecasis^*

^*Corresponding author for this work

Medical Sciences

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

138 Citations (Scopus)

Abstract

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (f case) = 0.51%; control frequency (f control) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (f case = 1.06%; f control = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Original language	English
Pages (from-to)	1375-1379
Number of pages	7
Journal	Nature Genetics
Volume	45
Issue number	11
Early online date	15 Sept 2013
DOIs	https://doi.org/10.1038/ng.2758
Publication status	Published - 1 Nov 2013

Bibliographical note

We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders.

Keywords

Diseaes
Genetic association study
Medical genetics
Sequencing

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Zhan, X., Larson, D. E., Wang, C., Koboldt, D. C., Sergeev, Y. V., Fulton, R. S., Fulton, L. L., Fronick, C. C., Branham, K. E., Bragg-Gresham, J., Jun, G., Hu, Y., Kang, H. M., Liu, D., Othman, M., Brooks, M., Ratnapriya, R., Boleda, A., Grassmann, F., ... Abecasis, G. R. (2013). Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nature Genetics, 45(11), 1375-1379. https://doi.org/10.1038/ng.2758

Zhan, X, Larson, DE, Wang, C, Koboldt, DC, Sergeev, YV, Fulton, RS, Fulton, LL, Fronick, CC, Branham, KE, Bragg-Gresham, J, Jun, G, Hu, Y, Kang, HM, Liu, D, Othman, M, Brooks, M, Ratnapriya, R, Boleda, A, Grassmann, F, Von Strachwitz, C, Olson, LM, Buitendijk, GHS, Hofman, A, Van Duijn, CM, Cipriani, V, Moore, AT, Shahid, H, Jiang, Y, Conley, YP, Morgan, DJ, Kim, IK, Johnson, MP, Cantsilieris, S, Richardson, AJ, Guymer, RH, Luo, H, Ouyang, H, Licht, C, Pluthero, FG, Zhang, MM, Zhang, K, Baird, PN, Blangero, J, Klein, ML, Farrer, LA, DeAngelis, MM, Weeks, DE, Gorin, MB, Yates, JRW, Klaver, CCW, Pericak-Vance, MA, Haines, JL, Weber, BHF, Wilson, RK, Heckenlively, JR, Chew, EY, Stambolian, D, Mardis, ER, Swaroop, A & Abecasis, GR 2013, 'Identification of a rare coding variant in complement 3 associated with age-related macular degeneration', Nature Genetics, vol. 45, no. 11, pp. 1375-1379. https://doi.org/10.1038/ng.2758

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abstract = "Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (f case) = 0.51%; control frequency (f control) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (f case = 1.06%; f control = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.",

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note = "We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders.",

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doi = "10.1038/ng.2758",

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journal = "Nature Genetics",

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T1 - Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

AU - Zhan, Xiaowei

AU - Larson, David E.

AU - Wang, Chaolong

AU - Koboldt, Daniel C.

AU - Sergeev, Yuri V.

AU - Fulton, Robert S.

AU - Fulton, Lucinda L.

AU - Fronick, Catrina C.

AU - Branham, Kari E.

AU - Bragg-Gresham, Jennifer

AU - Jun, Goo

AU - Hu, Youna

AU - Kang, Hyun Min

AU - Liu, Dajiang

AU - Othman, Mohammad

AU - Brooks, Matthew

AU - Ratnapriya, Rinki

AU - Boleda, Alexis

AU - Grassmann, Felix

AU - Von Strachwitz, Claudia

AU - Olson, Lana M.

AU - Buitendijk, Gabriëlle H.S.

AU - Hofman, Albert

AU - Van Duijn, Cornelia M.

AU - Cipriani, Valentina

AU - Moore, Anthony T.

AU - Shahid, Humma

AU - Jiang, Yingda

AU - Conley, Yvette P.

AU - Morgan, Denise J.

AU - Kim, Ivana K.

AU - Johnson, Matthew P.

AU - Cantsilieris, Stuart

AU - Richardson, Andrea J.

AU - Guymer, Robyn H.

AU - Luo, Hongrong

AU - Ouyang, Hong

AU - Licht, Christoph

AU - Pluthero, Fred G.

AU - Zhang, Mindy M.

AU - Zhang, Kang

AU - Baird, Paul N.

AU - Blangero, John

AU - Klein, Michael L.

AU - Farrer, Lindsay A.

AU - DeAngelis, Margaret M.

AU - Weeks, Daniel E.

AU - Gorin, Michael B.

AU - Yates, John R.W.

AU - Klaver, Caroline C.W.

AU - Pericak-Vance, Margaret A.

AU - Haines, Jonathan L.

AU - Weber, Bernhard H.F.

AU - Wilson, Richard K.

AU - Heckenlively, John R.

AU - Chew, Emily Y.

AU - Stambolian, Dwight

AU - Mardis, Elaine R.

AU - Swaroop, Anand

AU - Abecasis, Goncalo R.

N1 - We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (f case) = 0.51%; control frequency (f control) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (f case = 1.06%; f control = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

AB - Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (f case) = 0.51%; control frequency (f control) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (f case = 1.06%; f control = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

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KW - Genetic association study

KW - Medical genetics

KW - Sequencing

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DO - 10.1038/ng.2758

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EP - 1379

JO - Nature Genetics

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ER -

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

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Keywords

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