Age at menopause genetic risk score in relation to primary open-angle glaucoma in the Augmented GLAUGEN study

Abstract

Purpose: In women, later age at menopause has been inversely related to primary open angle glaucoma (POAG). We assessed whether a panel of single nucleotide polymorphisms (SNPs) that predict age at menopause was associated with POAG.

Methods: We included 8,188 women from the Nurses’ Health Study with data on age at menopause and genotypes from three platforms imputed to 5.9 million markers with the 1000 genomes reference panel. Among these, 416 were POAG cases and 6145 were controls derived from the Augmented Glaucoma Genes and Environment (GLAUGEN) study. We derived a weighted genetic risk score (GRS) for later age at menopause using the estimated effect from 19 genetic variants identified in a large scale meta-analysis (Stolk et al. Nature Genetics 2012). First, we assessed whether this GRS is related to age at menopause in the whole sample. Then, in the Augmented GLAUGEN dataset, we evaluated the association between this GRS and POAG after adjusting for age, platform and principal components.

Results: The weighted GRS was strongly associated with self-reported age at menopause (beta=1.01 [95% confidence interval: 0.89-1.13] increase in age per unit increase in GRS; p=1.61x10^-67). The median age at menopause was 49.78, 50.51 and 51.39 for the three increasing GRS tertiles, respectively. The age at menopause GRS was not associated with POAG (odds ratio=1.09 [95% confidence interval: 0.93-1.26] per unit increase in GRS; p=0.28).

Conclusions: SNPs that predict age at menopause are involved in DNA repair. Although collectively, they were not associated with POAG, we plan a larger analysis of the association of this GRS with POAG using the larger consortium data from NEIGHBORHOOD (National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database).