Age-related macular degeneration: genetics and biology coming together.
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.
Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109; email: larsf@umich.edu , goncalo@umich.edu.
Lars G
LG
Fritsche
Robert N
RN
Fariss
Dwight
D
Stambolian
Gonçalo R
GR
Abecasis
Christine A
CA
Curcio
Anand
A
Swaroop
D017242:Complement Factor H / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
D017242:Complement Factor H
blindness; complex disease; genetic susceptibility; neurodegeneration; retina