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. Age-related macular degeneration (AMD) is the leading blindness cause in western countries. Several genes encoding components of the complement pathway—including CFH, C2/BF, and C3—have been confirmed to be associated with AMD, as well as a region on 10q26 that encompasses two genes. Recent data have suggested that loss of LOC387715 on 10q26, mediated by an insertion/deletion (in/del) at its 3'UTR that destabilizes its message, is causally related with the disorder. We found that a common disease haplotype including the in/del and rs11200638 also has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. We propose a binary model where downregulation of LOC387715 and concomitant upregulation of HTRA1 best explain the risk associated with the 10q26 AMD region.