A genome-wide scan for age-related maculopathy and other ocular phenotypes in a sample from the Beaver Dam Eye Study (BDES)

Abstract

Abstract: : Purpose:Age-related maculopathy (ARM), a disease of degeneration of the retina that clusters in families leading to loss of central vision, has multifactorial etiology. To identify genetic loci for ARM a genome scan was undertaken on a selected sample from a well-defined cohort, the Beaver Dam Eye study. Methods:One hundred families (N=325 subjects) with at least 2 affected sibs, consisting of 257 sib pairs, were genotyped for 350 markers spanning the genome. Prior to conducting model-free linkage analysis, genotyping and Mendelian inconsistencies were identified using MARKERINFO (S.A.G.E.), and relationships reclassified, if necessary, using the data from the genome scan and the relationship testing program RELTEST (S.A.G.E.). SIBPAL2 (S.A.G.E., release 4.0) was used to conduct single-point and multipoint linkage analyses for ARM. The Wisconsin grading scheme was used to define a quantitative trait for ARM, which was the outcome in a model-free linkage analysis. Results:We have conducted linkage analyses of the data under several models which ranged from simple adjustments for covariates to more complex models that incorporated parameters from our prior segregation analyses, in order to identify the best-fitting biologically plausible model. For example, in one analysis the ARM outcome was adjusted for covariates: age, age₂, smoking status, drinking habits and diabetes. Under this model we observed that five chromosomes had markers that exceeded the empirical p = 0.05 genome-wide threshold significance level: chromosome 3 at markers GATA164B08 (p = 0.012) and D3S3053 (p = 0.018), chromosome 4 at marker D4S2366 (p = 0.049), chromosome 10 at D10S1208 (p = 0.022) and D10S212 (p = 0.023), chromosome 12 at D12S1300 (p = 0.0003) and PAH (p = 0.004), and chromosome 16 at markers D16S769 (p = 0.034), GATA67G11 (p = 0.068), and D16S2624 (p = 0.034). While a number of regions demonstrate suggestive evidence for linkage and warrant follow up, our most significant result was at marker D12S1300. Our analysis confirms the report of linkage on chromosome 12 in a prior genome scan by Weeks et al. (2000). Additional fine mapping is being conducted in regions that demonstrate putative evidence for linkage. Conclusion:These analyses will enable us to comprehend the genetic basis of ARM by identifying chromosomal regions linked to disease, a first step in the process of positional cloning.

Keywords: 308 age-related macular degeneration • 418 gene mapping • 457 linkage analysis