Abstract
Purpose: :
The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of three quantitative components of the POAG phenotype, intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR) and central corneal thickness (CCT).
Methods: :
Genome-wide multipoint variance components linkage analysis of maximum recorded IOP, CDR and CCT were conducted using data from a large multi-center study of extended, Caucasian POAG families from Australia and North America, including 1181 people from 22 extended pedigrees. Variance components analysis was conducted using SOLAR. A population ascertainment correction was used to correct for sampling bias and an empirical LOD adjustment applied to correct for any non-normal trait distributions. This study was conducted in accordance with tenets of the Declaration of Helsinki. Informed consent was obtained from all participants.
Results: :
All three traits showed evidence of significant heritability. Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.87 near marker D3S3672. Analysis of maximum recorded VCDR gave a peak LOD score of 4.02 between D3S1558 and D3S1569, which is coincident with the GLC1C locus on chromosome 3q. Multipoint analysis of minimum recorded CCT produced a peak LOD score of 3.97 near marker D15S118. Age, sex and their interactions as well as population of origin were included as covariates in all analyses.
Conclusions: :
Identification of glaucoma susceptibility genes has been hampered by the complexity of the disease, as well as the late age of onset. Using a different approach than the classical Mendelian analysis, we successfully mapped loci for three POAG endophenotypes with LOD scores ≥ 3.0, Thus, utilization of quantitative traits for identification of POAG susceptibility genes combined with the power of family based linkage analysis appears to be a viable option that has the potential for breaking through the barriers to finding new POAG genes.
Keywords: genetics • gene mapping • gene screening