Age-related macular degeneration: genetics and biology coming together

Annu Rev Genomics Hum Genet. 2014;15:151-71. doi: 10.1146/annurev-genom-090413-025610. Epub 2014 Apr 16.

Abstract

Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40-60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.

Keywords: blindness; complex disease; genetic susceptibility; neurodegeneration; retina.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Complement Factor H / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Macular Degeneration / genetics*
  • Macular Degeneration / pathology
  • Mutation
  • Polymorphism, Single Nucleotide / genetics*
  • Risk Factors

Substances

  • Complement Factor H