Abstract
The statistical power of genome-wide association (GWA) studies to detect risk alleles for human diseases is limited by the unfavorable ratio of SNPs to study subjects. This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status. However, GWA approaches fall short when many rare alleles may give rise to a common disease, or when the number of subjects that can be recruited is limited. Here, we demonstrate that this multiple testing problem can be overcome by a comparative genomics approach in which an initial genome-wide screen in a genetically amenable model organism is used to identify human orthologues that may harbor risk alleles for adult-onset primary open angle glaucoma (POAG). Glaucoma is a major cause of blindness, which affects over 60 million people worldwide. Several genes have been associated with juvenile onset glaucoma, but genetic factors that predispose to adult onset primary open angle glaucoma (POAG) remain largely unknown. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC). We selected 16 orthologous genes with 62 polymorphic markers and identified in two independent human populations two genes of the UPR that harbor POAG risk alleles, BIRC6 and PDIA5. Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention.
Highlights
primary open angle glaucoma (POAG) is the most prevalent form of glaucoma, and a major cause of irreversible blindness [1]
The first has identified intergenic polymorphic markers associated with POAG in a Japanese population, but these markers could not be linked to annotated genes [8], while another genome-wide association (GWA) study has implicated a common variant near CAV1 and CAV2 in POAG [9]
We identified SNPs associated with POAG in both the Salt Lake City and San Diego populations in PDIA5 (PDIR), a protein disulfide isomerase which facilitates the formation of disulfide bonds during protein folding and is associated with the unfolded protein response (UPR) (Tables S3 and S4), and in BIRC6 (BRUCE, APOLLON), which encodes a ubiquitin ligase that protects against apoptosis (Tables S5 and S6) [21,22]
Summary
POAG is the most prevalent form of glaucoma, and a major cause of irreversible blindness [1]. The first has identified intergenic polymorphic markers associated with POAG in a Japanese population, but these markers could not be linked to annotated genes [8], while another GWA study has implicated a common variant near CAV1 and CAV2 in POAG [9]. It is not uncommon for different GWA studies to discover different marker associations for the same phenotype. When disease status represents a large mutational target, i.e. many rare alleles can predispose to the same disease phenotype, it is unlikely that different populations capture the same low frequency alleles, and populations of different genetic backgrounds may harbor population-specific variants
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