Abstract
Purpose :
Age-related macular degeneration (AMD) is a complex progressive disease affecting the central vision of millions of people worldwide. Several risk factors for AMD have been identified, including age, smoking, and genetics. Multiple genome-wide association studies have identified more than 52 independent variants in 34 loci. However, concerning AMD, little is known about post-zygotic mutations that accumulate throughout aging. Post-zygotic mutations in nucleated blood cells lead to mosaic phenotypes with significant genomic differences. Recent studies identified Y chromosome abundance is a considerable risk factor for late-stage AMD, independent of age and other environmental factors.
Methods :
Building on these reports, we computed the abundance of X and Y chromosomes of all participants from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. Utilizing the BCFtools plugin MoChA, which uses the allelic and total intensities of genotyping chips, we computed the chromosomal abundance of sex chromosomes, excluding the pseudoautosomal regions. Furthermore, we computed a new, more accurate AMD status for replication using the UK biobank's general practice (GP) data.
Results :
After quality control, we identified a significant association between decreased chromosomal abundance and AMD in IAMDGC with the X chromosome in females (OR:0.86 and 95% CI:0.83-0.89, P=6.18x10-16) and Y in males (OR:0.84 and 95% CI:0.80-0.88, P: 3.83 x10-16). Utilizing our newly computed AMD status for the UK Biobank, we replicated the effect of X and Y chromosome mosaicism with similar effect sizes in females and males, respectively (OR:0.93, 95% CI:0.87-0.99, P=4x10-2 and OR:0.93, 95% CI:0.88-0.99, P=3x10-2). We further explored the role of chromosomal abundance in disease severity and progression, revealing a significant association between Y abundance and Geographic Atrophy lesion size change (P value: 5x10-3).
Conclusions :
In conclusion, we present significant associations of the chromosomal abundance of sex chromosomes with overall AMD risk and its sub-types independent of confounding factors, as well as evidence that Y abundance can be considered a significant risk factor for Geographic Atrophy severity for males. Taken all together, chromosomal abundance is a significant risk factor for Age-related macular degeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.