Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration

Zhenglin Yang; Zongzhong Tong; Yuhong Chen; Jiexi Zeng; Fang Lu; Xufang Sun; Chao Zhao; Kevin Wang; Lisa Davey; Haoyu Chen; Nyall London; Daisuke Muramatsu; Francesca Salasar; Ruben Carmona; Daniel Kasuga; Xiaolei Wang; Matthew Bedell; Manjuxia Dixie; Peiquan Zhao; Ruifu Yang; Daniel Gibbs; Xiaoqi Liu; Yan Li; Cai Li; Yuanfeng Li; Betsy Campochiaro; Ryan Constantine; Donald J. Zack; Peter Campochiaro; Yinbin Fu; Dean Y. Li; Nicholas Katsanis; Kang Zhang

doi:10.1371/journal.pgen.1000836

Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration

Zhenglin Yang, Zongzhong Tong, Yuhong Chen, Jiexi Zeng, Fang Lu, Xufang Sun, Chao Zhao, Kevin Wang, Lisa Davey, Haoyu Chen, Nyall London, Daisuke Muramatsu, Francesca Salasar, Ruben Carmona, Daniel Kasuga, Xiaolei Wang, Matthew Bedell, Manjuxia Dixie, Peiquan Zhao, Ruifu YangDaniel Gibbs, Xiaoqi Liu, Yan Li, Cai Li, Yuanfeng Li, Betsy Campochiaro, Ryan Constantine, Donald J. Zack, Peter Campochiaro, Yinbin Fu, Dean Y. Li, Nicholas Katsanis, Kang Zhang

School of Medicine

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

82 Scopus citations

Abstract

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/ del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

Original language	English (US)
Article number	e1000836
Journal	PLoS genetics
Volume	6
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1000836
State	Published - Feb 2010

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

Access to Document

10.1371/journal.pgen.1000836

Cite this

Yang, Z., Tong, Z., Chen, Y., Zeng, J., Lu, F., Sun, X., Zhao, C., Wang, K., Davey, L., Chen, H., London, N., Muramatsu, D., Salasar, F., Carmona, R., Kasuga, D., Wang, X., Bedell, M., Dixie, M., Zhao, P., ... Zhang, K. (2010). Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS genetics, 6(2), Article e1000836. https://doi.org/10.1371/journal.pgen.1000836

Yang, Z, Tong, Z, Chen, Y, Zeng, J, Lu, F, Sun, X, Zhao, C, Wang, K, Davey, L, Chen, H, London, N, Muramatsu, D, Salasar, F, Carmona, R, Kasuga, D, Wang, X, Bedell, M, Dixie, M, Zhao, P, Yang, R, Gibbs, D, Liu, X, Li, Y, Li, C, Li, Y, Campochiaro, B, Constantine, R, Zack, DJ , Campochiaro, P, Fu, Y, Li, DY, Katsanis, N & Zhang, K 2010, 'Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration', PLoS genetics, vol. 6, no. 2, e1000836. https://doi.org/10.1371/journal.pgen.1000836

@article{3091c42609e14f918b6df3d0ca32a60e,

title = "Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration",

abstract = "A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/ del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.",

author = "Zhenglin Yang and Zongzhong Tong and Yuhong Chen and Jiexi Zeng and Fang Lu and Xufang Sun and Chao Zhao and Kevin Wang and Lisa Davey and Haoyu Chen and Nyall London and Daisuke Muramatsu and Francesca Salasar and Ruben Carmona and Daniel Kasuga and Xiaolei Wang and Matthew Bedell and Manjuxia Dixie and Peiquan Zhao and Ruifu Yang and Daniel Gibbs and Xiaoqi Liu and Yan Li and Cai Li and Yuanfeng Li and Betsy Campochiaro and Ryan Constantine and Zack, {Donald J.} and Peter Campochiaro and Yinbin Fu and Li, {Dean Y.} and Nicholas Katsanis and Kang Zhang",

year = "2010",

month = feb,

doi = "10.1371/journal.pgen.1000836",

language = "English (US)",

volume = "6",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "2",

}

TY - JOUR

T1 - Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration

AU - Yang, Zhenglin

AU - Tong, Zongzhong

AU - Chen, Yuhong

AU - Zeng, Jiexi

AU - Lu, Fang

AU - Sun, Xufang

AU - Zhao, Chao

AU - Wang, Kevin

AU - Davey, Lisa

AU - Chen, Haoyu

AU - London, Nyall

AU - Muramatsu, Daisuke

AU - Salasar, Francesca

AU - Carmona, Ruben

AU - Kasuga, Daniel

AU - Wang, Xiaolei

AU - Bedell, Matthew

AU - Dixie, Manjuxia

AU - Zhao, Peiquan

AU - Yang, Ruifu

AU - Gibbs, Daniel

AU - Liu, Xiaoqi

AU - Li, Yan

AU - Li, Cai

AU - Li, Yuanfeng

AU - Campochiaro, Betsy

AU - Constantine, Ryan

AU - Zack, Donald J.

AU - Campochiaro, Peter

AU - Fu, Yinbin

AU - Li, Dean Y.

AU - Katsanis, Nicholas

AU - Zhang, Kang

PY - 2010/2

Y1 - 2010/2

N2 - A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/ del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

AB - A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/ del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

UR - http://www.scopus.com/inward/record.url?scp=77649217229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77649217229&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1000836

DO - 10.1371/journal.pgen.1000836

M3 - Article

C2 - 20140183

AN - SCOPUS:77649217229

SN - 1553-7390

VL - 6

JO - PLoS genetics

JF - PLoS genetics

IS - 2

M1 - e1000836

ER -

Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this