• age related macular degeneration (AMD);
  • complement pathway;
  • false discovery rate (FDR);
  • pathway-based disease association;
  • single nucleotide polymorphisms (SNP)


In this paper we explore the use of biological knowledge to supplement statistical analysis in identifying genes associated with disease. It has been previously found that the 402H variant in complement factor H (CFH) is associated with risk for developing age related macular degeneration (AMD). By focusing on the single nucleotide polymorphisms (SNPs) in the complement pathway, we were able to use the genotype data from a recently published AMD genome wide association study to identify two additional genes, C7 and MBL2, as potentially associated with subtypes of AMD. Two SNPs situated in introns of C7 and MBL2 could help differentiate between two forms of AMD: wet (more severe form of AMD) and dry (milder form of AMD). We identified a C7 haplotype associated with protection against developing wet AMD among individuals with homozygous CFH risk allele 402H (p-value 0.001 for wet AMD versus dry AMD, odds ratio (OR) 0.16, OR 95% CI 0.05–0.49) as well as among individuals with at least one CFH risk allele (p-value 0.007 for wet AMD versus dry AMD, OR 0.35, OR 95% CI 0.16–0.77). The fact that the statistical scores for the C7 and MBL2 SNPs were significant (low false discovery rate) at the pathway level, but not significant at the genome level suggests that focusing at the pathway level can be beneficial for identifying SNP signals that would be lost at the genome-wide level. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc.