gms | German Medical Science

Background: Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in industrialized countries. Little is known, however, about the molecular biology underlying the disease. Deciphering the genetic architecture contributing to AMD pathology has been extremely successful in recent years and has established a spectrum of pathways involved in disease aetiology.

Methods: Single nucleotide polymorphism-based genetic association studies were done in non-directed genome-wide scans (GWAS). For meta-GWAS, summary statistics such as ß- and P-values were combined from individual independent studies. The International AMD Genomics Consortium directly genotyped 163,714 protein-altering variants, mostly rare, and >11 million other variants, mostly common, in 16,144 advanced AMD cases and 17,832 controls.

Results: To date, at least 34 genetic loci have reliably been identified together accounting for at least 52 independent risk variants associated with late stage AMD. Major effects have been noted at the CFH on chromosome 1q32 and at ARMS2 / HTRA1 on 10q26. A crucial role of the complement system in AMD was also emphasized by associated risk variants in or near additional complement genes such as C2/CFB, C3, C9 and CFI. Other pathways suggesting a role of cholesterol and lipid metabolism in AMD as well as homeostatic disturbances in the extracellular matrix were pinpointed by the recent studies.

Conclusions: Insight into AMD genetics including rare protein-altering variants has the potential to improve our understanding of genetic variation in macular degeneration biology, so as to guide the development of therapeutic intervention and facilitate early diagnosis, monitoring and prevention of the disease.