A Susceptibility Locus for Age–Related Macular Degeneration on Chromosome 16p12

Abstract

Purpose: : Age–related macular degeneration (AMD) is a common, multifactorial disease that causes central visual acuity to deteriorate in affected individuals and may lead to legal blindness. A strong genetic component has long been suspected in the etiology of AMD based on results from familial aggregation studies, segregation analysis, and genomic screens. With the identification of the Y402H susceptibility variant in the CFH gene and increasing reports of the association between a variant in LOC387715 with AMD risk, locus heterogeneity must be considered in the search for additional AMD genes. In addition to chromosomes 1 and 10, where CFH and LOC387715 are located, chromosome 16 has also been implicated in AMD risk (Schick et al. 2003, Iyengar et al. 2004, Schmidt et al. 2004, and Fisher et al. 2005).

Methods: : To localize this gene we genotyped 130 SNPs across 11 Mb on 16p12 in 530 cases and 223 controls and an independent family–based dataset of 201 families. We first calculated the baseline LOD* and then Ordered Subset Analysis(OSA) was used to examine the impact of various covariates on the evidence for linkage to chromosome 16.

Results: : We observed a peak LOD* of 0.9 at 44.7 cM. Using OSA to take into account the effect of the CFH gene, the LOD* on chromosome 16 rose substantially to 2.4 arising primarily from a subset of 20 families ranked from high to low on Y402H LOD* (p = 0.07). OSA analysis considering the LOD* score at LOC387715 rs10490924 and average pack–years of cigarette smoking as the covariates did not significantly change the baseline LOD* score.

Conclusions: : These results refine the location of the chromosome 16 gene and demonstrate the importance of considering known disease risk factors as covariates when conducting linkage analysis.

Keywords: age-related macular degeneration • genetics