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 & 40 others 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

Research output: Contribution to journalLetter

95 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 languageEnglish (US)
Pages (from-to)1375-1381
Number of pages7
JournalNature Genetics
Volume45
Issue number11
DOIs
StatePublished - Nov 1 2013

Fingerprint

Complement C3
Macular Degeneration
Odds Ratio
Exome
Alternative Complement Pathway
Complement Factor H
Blindness
Gene Frequency
Genes
Macular Degeneration, Age-Related, 2

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Zhan, X., Larson, D. E., Wang, C., Koboldt, D. C., Sergeev, Y. V., Fulton, R. S., ... 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
Zhan, Xiaowei ; Larson, David E. ; Wang, Chaolong ; Koboldt, Daniel C. ; Sergeev, Yuri V. ; Fulton, Robert S. ; Fulton, Lucinda L. ; Fronick, Catrina C. ; Branham, Kari E. ; Bragg-Gresham, Jennifer ; Jun, Goo ; Hu, Youna ; Kang, Hyun Min ; Liu, Dajiang ; Othman, Mohammad ; Brooks, Matthew ; Ratnapriya, Rinki ; Boleda, Alexis ; Grassmann, Felix ; Von Strachwitz, Claudia ; Olson, Lana M. ; Buitendijk, Gabriëlle H.S. ; Hofman, Albert ; Van Duijn, Cornelia M. ; Cipriani, Valentina ; Moore, Anthony T. ; Shahid, Humma ; Jiang, Yingda ; Conley, Yvette P. ; Morgan, Denise J. ; Kim, Ivana K. ; Johnson, Matthew P. ; Cantsilieris, Stuart ; Richardson, Andrea J. ; Guymer, Robyn H. ; Luo, Hongrong ; Ouyang, Hong ; Licht, Christoph ; Pluthero, Fred G. ; Zhang, Mindy M. ; Zhang, Kang ; Baird, Paul N. ; Blangero, John ; Klein, Michael L. ; Farrer, Lindsay A. ; DeAngelis, Margaret M. ; Weeks, Daniel E. ; Gorin, Michael B. ; Yates, John R.W. ; Klaver, Caroline C.W. ; Pericak-Vance, Margaret A. ; Haines, Jonathan L. ; Weber, Bernhard H.F. ; Wilson, Richard K. ; Heckenlively, John R. ; Chew, Emily Y. ; Stambolian, Dwight ; Mardis, Elaine R. ; Swaroop, Anand ; Abecasis, Goncalo R. / Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. In: Nature Genetics. 2013 ; Vol. 45, No. 11. pp. 1375-1381.
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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.",
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.}",
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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

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. / Zhan, Xiaowei; Larson, David E.; Wang, Chaolong; Koboldt, Daniel C.; Sergeev, Yuri V.; Fulton, Robert S.; Fulton, Lucinda L.; Fronick, Catrina C.; Branham, Kari E.; Bragg-Gresham, Jennifer; Jun, Goo; Hu, Youna; Kang, Hyun Min; Liu, Dajiang; Othman, Mohammad; Brooks, Matthew; Ratnapriya, Rinki; Boleda, Alexis; Grassmann, Felix; Von Strachwitz, Claudia; Olson, Lana M.; Buitendijk, Gabriëlle H.S.; Hofman, Albert; Van Duijn, Cornelia M.; Cipriani, Valentina; Moore, Anthony T.; Shahid, Humma; Jiang, Yingda; Conley, Yvette P.; Morgan, Denise J.; Kim, Ivana K.; Johnson, Matthew P.; Cantsilieris, Stuart; Richardson, Andrea J.; Guymer, Robyn H.; Luo, Hongrong; Ouyang, Hong; Licht, Christoph; Pluthero, Fred G.; Zhang, Mindy M.; Zhang, Kang; Baird, Paul N.; Blangero, John; Klein, Michael L.; Farrer, Lindsay A.; DeAngelis, Margaret M.; Weeks, Daniel E.; Gorin, Michael B.; Yates, John R.W.; Klaver, Caroline C.W.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Weber, Bernhard H.F.; Wilson, Richard K.; Heckenlively, John R.; Chew, Emily Y.; Stambolian, Dwight; Mardis, Elaine R.; Swaroop, Anand; Abecasis, Goncalo R.

In: Nature Genetics, Vol. 45, No. 11, 01.11.2013, p. 1375-1381.

Research output: Contribution to journalLetter

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 - 2013/11/1

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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DO - 10.1038/ng.2758

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JF - Nature Genetics

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Zhan X, Larson DE, Wang C, Koboldt DC, Sergeev YV, Fulton RS et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nature Genetics. 2013 Nov 1;45(11):1375-1381. https://doi.org/10.1038/ng.2758