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 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

Department of Ophthalmology

University of Michigan, Ann Arbor
Washington University St. Louis
Harvard University
National Institutes of Health
University of Regensburg
EyeCentre Southwest
Vanderbilt University
Erasmus University Rotterdam
Netherlands Consortium for Healthy Aging
University College London
Moorfields Eye Hospital NHS Foundation Trust
University of Cambridge
Cambridge University Hospitals NHS Foundation Trust
University of Pittsburgh
University of Utah
Massachusetts Eye and Ear
Southwest Foundation for Biomedical Research
University of Melbourne
University of California at San Diego
University of Toronto
Oregon Health and Science University
Boston University
University of California at Los Angeles
University of Miami
University of Pennsylvania

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

149 Scopus citations

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)	1375-1381
Number of pages	7
Journal	Nature Genetics
Volume	45
Issue number	11
DOIs	https://doi.org/10.1038/ng.2758
State	Published - Nov 2013

Access to Document

10.1038/ng.2758

Cite this

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), 1375-1381. https://doi.org/10.1038/ng.2758

@article{e8163010f17245e8b4a0f7f49d618994,

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

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.",

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

year = "2013",

month = nov,

doi = "10.1038/ng.2758",

language = "English",

volume = "45",

pages = "1375--1381",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

}

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. 1375-1381. https://doi.org/10.1038/ng.2758

TY - JOUR

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.

PY - 2013/11

Y1 - 2013/11

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.

UR - https://www.scopus.com/pages/publications/84887118518

U2 - 10.1038/ng.2758

DO - 10.1038/ng.2758

M3 - Letter

C2 - 24036949

AN - SCOPUS:84887118518

SN - 1061-4036

VL - 45

SP - 1375

EP - 1381

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this