Genetic and Functional Dissection of HTRA1 and LOC387715 in Age-Related Macular Degeneration: e1000836

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...

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Published in:PLoS genetics 2010-02, Vol.6 (2)
Main Authors: Yang, Zhenglin, Tong, Zongzhong, Chen, Yuhong, Zeng, Jiexi, Lu, Fang, Sun, Xufang, Zhao, Chao, Wang, Kevin, Davey, Lisa, Chen, Haoyu, London, Nyall, Muramatsu, Daisuke, Salasar, Francesca, Carmona, Ruben, Kasuga, Daniel, Wang, Xiaolei, Bedell, Matthew, Dixie, Manjuxia, Zhao, Peiquan, Yang, Ruifu, Gibbs, Daniel, Liu, Xiaoqi, Li, Yan, Li, Cai, Li, Yuanfeng, Campochiaro, Betsy, Constantine, Ryan, Zack, Donald J, Campochiaro, Peter, Fu, Yinbin, Li, Dean Y, Katsanis, Nicholas, Zhang, Kang
Format: Article
Language:English
Subjects:
Genes
Genomes
Haplotypes
Macular degeneration
Pathogenesis
Plasmids
Studies
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Summary: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.
ISSN:1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000836