A High Density SNP Genome Screen for Age Related Macular Degeneration Reveals Novel Loci

Abstract

Purpose: : Age related macular degeneration is a complex inherited disorder. Here we report a SNP–based genome–wide screen on a large AMD family dataset.

Methods: : A genome–wide screen was performed on a dataset of 364 individuals from 127 multiplex AMD families. The Illumina Bead Station platform (Linkage Panel IV) was used to genotype 5253 single nucleotide polymorphisms (SNPs). For multipoint analyses a single SNP was selected from each bin of SNPs in linkage disequilibrium (r2 > 0.16). Both parametric and non parametric analyses were performed.

Results: : This analysis replicates previous linkages, including the regions on 1q containing the Complement Factor H gene, and on 10q containing the LOC388715 gene, both of which play a major role in the genetic susceptibility to AMD. Linkage to chromosome 9 replicates findings from two other groups. We have previously identified linkage to chromosomes 14 and 16 by using ordered subsets analysis (OSA) to stratify a microsatellite genome scan by clinical measures including intraocular pressure, systolic blood pressure and body mass index. Application of OSA to the new linkage data significantly increases the lod score on chromsome 14 from 1.55 to 4.1 in a clinically distinct subset of 61 families (p=0.017). In addition, this new genome scan identifies novel linkage peaks with multipoint lod scores greater than 1.0 on chromosomes 3, 6, 13, and 22. The most interesting novel linkage is on chromosome 20 with a lod* >3.0. These linkage regions are being further examined using both family based and case/control association analyses.

Conclusions: : We have used a high–density SNP–based genome scan to confirm previous loci and identified several novel loci linked to AMD. This work continues the rapid dissection of the genetic underpinnings of AMD, which will lead to new therapeutic interventions to help prevent blindness in millions of AMD patients.

Keywords: linkage analysis • macula/fovea • age-related macular degeneration