Dan Weeks

BackgroundAge-related macular degeneration (AMD) is a complex disorder that is responsible for the majority of central vision loss in older adults living in developed countries. Phenotypic and genetic heterogeneity complicate the analysis of genome-wide scans for AMD susceptibility loci. The ordered subset analysis (OSA) method is an approach for reducing heterogeneity, increasing statistical power for detecting linkage, and helping to define the most informative data set for follow-up analysis. OSA assesses the linkage evidence in subsets of potentially more homogeneous families by rank-ordering family-specific lod scores with respect to trait-associated covariates or phenotypic features. Here, we present results of incorporating five continuous covariates into our genome-wide linkage analysis of 389 microsatellite markers in 62 multiplex families: Body mass index (BMI), systolic (SBP) and diastolic (DBP) blood pressure, intraocular pressure (IOP), and pack-years of cigarette smoking. Chromosome-wide significance of increases in nonparametric multipoint lod scores in covariate-defined subsets relative to the overall sample was assessed by permutation.ResultsUsing a correction for testing multiple covariates, statistically significant lod score increases were observed for two chromosomal regions: 14q13 with a lod score of 3.2 in 28 families with average IOP ≤ 15.5 (p = 0.002), and 6q14 with a lod score of 1.6 in eight families with average BMI ≥ 30.1 (p = 0.0004). On chromosome 16p12, nominally significant lod score increases (p ≤ 0.05), up to a lod score of 2.9 in 32 families, were observed with several covariate orderings. While less significant, this was the only region where linkage evidence was associated with multiple clinically meaningful covariates and the only nominally significant finding when analysis was restricted to advanced forms of AMD. Families with linkage to 16p12 had higher averages of SBP, IOP and BMI and were primarily affected with neovascular AMD. For all three regions, linkage signals at or very near the peak marker have previously been reported.ConclusionOur results suggest that a susceptibility gene on chromosome 16p12 may predispose to AMD, particularly to the neovascular form, and that further research into the previously suggested association of neovascular AMD and systemic hypertension is warranted.

Multiple genome-wide scans involving sib-pairs or limited pedigrees have been extensively used for a wide number of complex genetic conditions. Comparing data from two or more scans, as well as combining data, require an understanding of the sources of genotyping errors and data discrepancies. We have conducted two genome-wide scans for age-related maculopathy using the Center for Inherited Disease Research (CIDR) and the Mammalian Genotyping Service (MGS). Thirty individuals were typed in common, in order to allow for the alignment of alleles and comparison of the data sets. The analysis of these 8914 genotypes distributed over 321 markers in common demonstrated excellent agreement between these two laboratories, which have low rates of internal errors. Under the assumption that within each genotype, the smaller MGS allele should correspond to the smaller CIDR allele, the alleles align well between the two centers, with only a small fraction (less than 0.65%) of the aligned alleles showing large differences in sizes. However, since called allele sizes are integer "labels" which may not directly reflect the true underlying allele sizes, it is important to carefully prepare in advance if one wishes to merge data from different laboratories. In particular, it would not suffice to attempt to align alleles by typing only one or two controls in common. Fortunately, for the purposes of linkage analysis, one can avoid merging difficulties by simply carrying out linkage analyses using laboratory-specific allele labels and allele frequencies for each laboratory-specific subset of the data.