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

XW Zhan; DE Larson; CL Wang; DC Koboldt; YV Sergeev; RS Fulton; LL Fulton; CC Fronick; KE Branham; J Bragg-Gresham; G Jun; YN Hu; HM Kang; DJ Liu; M Othman; M Brooks; R Ratnapriya; A Boleda; F Grassmann; C von Strachwitz; LM Olson; Gabriëlle Buitendijk; Bert Hofman; Cornelia Duijn; V Cipriani; AT Moore; H Shahid; YD Jiang; YP Conley; DJ Morgan; IK Kim; MP Johnson; S Cantsilieris; AJ Richardson; RH Guymer; HR Luo; H Ouyang; C Licht; FG Pluthero; MM Zhang; Kai Zhang; PN Baird; J Blangero; ML Klein; LA Farrer; MM DeAngelis; DE Weeks; MB Gorin; JRW Yates; Caroline Klaver; MA Pericak-Vance; JL Haines; BHF Weber; RK Wilson; JR Heckenlively; EY Chew; D Stambolian; ER Mardis; A Swaroop; GR Abecasis

doi:10.1038/ng.2758

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

XW Zhan, DE Larson, CL Wang, DC Koboldt, YV Sergeev, RS Fulton, LL Fulton, CC Fronick, KE Branham, J Bragg-Gresham, G Jun, YN Hu, HM Kang, DJ Liu, M Othman, M Brooks, R Ratnapriya, A Boleda, F Grassmann, C von StrachwitzLM Olson, Gabriëlle Buitendijk, Bert Hofman, Cornelia Duijn, V Cipriani, AT Moore, H Shahid, YD Jiang, YP Conley, DJ Morgan, IK Kim, MP Johnson, S Cantsilieris, AJ Richardson, RH Guymer, HR Luo, H Ouyang, C Licht, FG Pluthero, MM Zhang, Kai Zhang, PN Baird, J Blangero, ML Klein, LA Farrer, MM DeAngelis, DE Weeks, MB Gorin, JRW Yates, Caroline Klaver, MA Pericak-Vance, JL Haines, BHF Weber, RK Wilson, JR Heckenlively, EY Chew, D Stambolian, ER Mardis, A Swaroop, GR Abecasis

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

139 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	Undefined/Unknown
Pages (from-to)	1375-+
Journal	Nature Genetics
Volume	45
Issue number	11
DOIs	https://doi.org/10.1038/ng.2758
Publication status	Published - 2013

Research programs

EMC NIHES-01-64-01
EMC OR-01-60-01

Access to Document

10.1038/ng.2758

http://hdl.handle.net/1765/54115

Cite this

Zhan, XW., Larson, DE., Wang, CL., Koboldt, DC., Sergeev, YV., Fulton, RS., Fulton, LL., Fronick, CC., Branham, KE., Bragg-Gresham, J., Jun, G., Hu, YN., Kang, HM., Liu, DJ., Othman, M., Brooks, M., Ratnapriya, R., Boleda, A., Grassmann, F., ... Abecasis, GR. (2013). Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nature Genetics, 45(11), 1375-+. https://doi.org/10.1038/ng.2758

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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 = "XW Zhan and DE Larson and CL Wang and DC Koboldt and YV Sergeev and RS Fulton and LL Fulton and CC Fronick and KE Branham and J Bragg-Gresham and G Jun and YN Hu and HM Kang and DJ Liu and M Othman and M Brooks and R Ratnapriya and A Boleda and F Grassmann and {von Strachwitz}, C and LM Olson and Gabri{\"e}lle Buitendijk and Bert Hofman and Cornelia Duijn and V Cipriani and AT Moore and H Shahid and YD Jiang and YP Conley and DJ Morgan and IK Kim and MP Johnson and S Cantsilieris and AJ Richardson and RH Guymer and HR Luo and H Ouyang and C Licht and FG Pluthero and MM Zhang and Kai Zhang and PN Baird and J Blangero and ML Klein and LA Farrer and MM DeAngelis and DE Weeks and MB Gorin and JRW Yates and Caroline Klaver and MA Pericak-Vance and JL Haines and BHF Weber and RK Wilson and JR Heckenlively and EY Chew and D Stambolian and ER Mardis and A Swaroop and GR Abecasis",

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Zhan, XW, Larson, DE, Wang, CL, Koboldt, DC, Sergeev, YV, Fulton, RS, Fulton, LL, Fronick, CC, Branham, KE, Bragg-Gresham, J, Jun, G, Hu, YN, Kang, HM, Liu, DJ, Othman, M, Brooks, M, Ratnapriya, R, Boleda, A, Grassmann, F, von Strachwitz, C, Olson, LM, Buitendijk, G, Hofman, B, Duijn, C, Cipriani, V, Moore, AT, Shahid, H, Jiang, YD, Conley, YP, Morgan, DJ, Kim, IK, Johnson, MP, Cantsilieris, S, Richardson, AJ, Guymer, RH, Luo, HR, 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, C, 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-+. 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, XW

AU - Larson, DE

AU - Wang, CL

AU - Koboldt, DC

AU - Sergeev, YV

AU - Fulton, RS

AU - Fulton, LL

AU - Fronick, CC

AU - Branham, KE

AU - Bragg-Gresham, J

AU - Jun, G

AU - Hu, YN

AU - Kang, HM

AU - Liu, DJ

AU - Othman, M

AU - Brooks, M

AU - Ratnapriya, R

AU - Boleda, A

AU - Grassmann, F

AU - von Strachwitz, C

AU - Olson, LM

AU - Buitendijk, Gabriëlle

AU - Hofman, Bert

AU - Duijn, Cornelia

AU - Cipriani, V

AU - Moore, AT

AU - Shahid, H

AU - Jiang, YD

AU - Conley, YP

AU - Morgan, DJ

AU - Kim, IK

AU - Johnson, MP

AU - Cantsilieris, S

AU - Richardson, AJ

AU - Guymer, RH

AU - Luo, HR

AU - Ouyang, H

AU - Licht, C

AU - Pluthero, FG

AU - Zhang, MM

AU - Zhang, Kai

AU - Baird, PN

AU - Blangero, J

AU - Klein, ML

AU - Farrer, LA

AU - DeAngelis, MM

AU - Weeks, DE

AU - Gorin, MB

AU - Yates, JRW

AU - Klaver, Caroline

AU - Pericak-Vance, MA

AU - Haines, JL

AU - Weber, BHF

AU - Wilson, RK

AU - Heckenlively, JR

AU - Chew, EY

AU - Stambolian, D

AU - Mardis, ER

AU - Swaroop, A

AU - Abecasis, GR

PY - 2013

Y1 - 2013

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.

U2 - 10.1038/ng.2758

DO - 10.1038/ng.2758

M3 - Article

C2 - 24036949

SN - 1061-4036

VL - 45

SP - 1375-+

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -