Purpose: To investigate a potential genetic contribution to intraocular pressure (IOP), we performed a complex segregation analysis on 2337 individuals in 620 extended pedigrees ascertained through a population-based cohort, the Beaver Dam Eye Study (BDES). IOP is a principal risk factor for primary open-angle glaucoma (POAG) a leading cause of blindness worldwide.
Methods: Segregation analysis is an analytical method that provides statistical evidence supporting the involvement of a major gene or polygenes in a particular phenotype. Detailed medical histories and eye examinations were performed on all participants. From the two eyes, the higher IOP measurement was used as a continuous trait after adjustment for covariates. A genome-wide scan (GWS) using affected sib pair linkage analysis was performed on 218 sibling pairs.
Results: In this segregation analysis the model that allowed for an unmeasured major environmental effect plus a polygenic/multifactorial effect provided the best fit and was the most parsimonious model. The lack of an adequate fit for the Mendelian single-gene models is consistent with a multifactorial model of inheritance that may include multiple genes and environmental factors that contribute to IOP. The results of the GWS yielded two novel loci as potential linkage regions for IOP on chromosomes 6 (P = 0.008) and 13 (P = 0.0007). Neither of these regions has previously been identified in GWS of POAG.
Conclusions: The segregation and familial correlation analyses of IOP suggest a polygenetic component with environmental influences. The pilot linkage study further confirms the heterogeneity of IOP with the identification of two novel genetic loci.