Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration

Abstract

Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2g = 0.42 ± 0.09) and AMD (h2g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.

Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits

“…Testing our dataset for this possibility showed that the association of the genetic scores in the population-based studies remained unchanged when comparing to the entire data including case-control studies with the exception of the VCDR and MYP genetic scores. From this, we conclude that AMD patients indeed have a genetically reduced risk to develop open angle glaucoma, although a smaller study found an adverse relationship between AMD and POAG using summary statistics [110]. Conversely, we found no association of the myopia genetic score with AMD in our dataset in the population-based studies, in line with previous reports [111–114].…”

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

“…Analyses of firstdegree relatives of POAG patients have shown that the sib relative risk is 10.4 6 2.5 (5). Classic twin studies in POAG are lacking and there is no consensus on heritability for POAG, but work by Cuellar-Partida et al estimated the heritability of POAG based on genome-wide array data at 0.42 6 0.09 (6). Several genome-wide association studies (GWAS) have identified new POAG genes by examining POAG directly or studying endophenotypes like VCDR and IOP (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Author Response: Stronger Association of CDKN2B-AS1 Variants in Female Normal-Tension Glaucoma Patients in a Japanese Population

“…4 We found that the genetic correlation estimated from markers genome-wide was substantially less than 1 (correlation 0.33, with standard error 0.24). Our findings on POAG are in contrast to findings across other complex traits, where the genome-wide genetic correlation between males and females is typically close to 1.…”

“…It is also likely that some of the difference in POAG prevalence between sexes is due to heritable factors. However, as for our finding at 9p21 we have only estimated the genome-wide genetic correlation in one population (Australians of European ancestry 4 ). It would be interesting to investigate sex differences genome-wide in other populations.…”

“…For example, in age-related macular degeneration, the genetic correlation is not significantly different to 1 (estimated to be 0.71, with standard error 0.23). 4 It should be emphasized that a higher prevalence in one sex does not prohibit there being a very high genetic correlation; for example, in esophageal cancer there are eight times as many male as female cases, and yet the genetic correlation is estimated to be 1. 5 A low genetic correlation between the sexes implies that a proportion of the genetic variants that influence POAG risk in one sex have little or no effect in the opposite sex.…”