Table 1.
Common age-related macular degeneration (AMD) variants with known molecular effects and associated mechanisms.
| Risk variant | Study references | Population/Type of cases | Effect of variant | Implicated mechanisms contributing to AMD |
|---|---|---|---|---|
| ARMS2-HTRA1 rs10490924 | (DeWan et al., 2006) | Asia (Hong Kong)/wet AMD | In linkage disequilibrium with rs11200638; surrogate marker for functional polymorphism rs11200638 (DeWan et al., 2006) | – |
| (Fritsche et al., 2013) | Europe and Asia (Meta-analysis of GWAS)/advanced AMD | |||
| (Yu et al., 2011) | Europe (Meta-analysis of GWAS)/advanced AMD | |||
| (Cheng et al., 2015) | East Asia/wet AMD | |||
| HTRA1 rs11200638 | (DeWan et al., 2006) | Asia (Hong Kong)/wet AMD | Increase in HTRA1 mRNA and protein [in RPE (DeWan, et al., 2006; Yang et al., 2006), in aqueous humor (Tosi et al., 2017) and in drusen (DeWan et al., 2006; Yang et al., 2006)] | Higher HTRA1 levels increase activity of degradative ECM enzymes and compromise Bruch membrane integrity, favoring choroidal invasion (Yang et al., 2006; Jones et al., 2011). |
| CFH rs10737680 | (Fritsche et al., 2013) | Europe and Asia (Meta-analysis of GWAS)/advanced AMD | Loss of function mutation in CFH which disrupts binding of CFH to C3b [Reported for common allele CFH Y402H and rare penetrant allele R1210C] (Clark et al., 2010; Clark et al., 2013; Manuelian et al., 2003; Ferreira et al., 2009; Weismann et al., 2011) | Decreased CFH inhibition of C3b results in increased alternative complement pathway activation [Reported for common allele CFH Y402H and rare penetrant allele R1210C] (Clark et al., 2010; Clark et al., 2013; Manuelian et al., 2003; Ferreira et al., 2009; Weismann et al., 2011) |
| (Cheng et al., 2015) | East Asia/wet AMD | |||
| C3 rs2230199 | (Fritsche et al., 2013) | Europe and Asia (Meta-analysis of GWAS)/advanced AMD | Alteration of configuration of first ring of macroglobulin domains, reducing binding of C3 to CFH (protein studies using electron microscopy) (Nishida et al., 2006; Zhang et al., 2018) | Reduced C3 binding to CFH increases complement activation (Zhang et al., 2018) |
Amongst the large repertoire of AMD single nucleotide polymorphisms (SNPs) generated by genome wide association studies (GWAS), several such as ARMS2-HTRA1 rs10490924, HTRA1 rs11200638, CFH rs10737680, and C3 rs2230199 have been further interrogated for their molecular effects and mechanisms leading to AMD.