Genetic epidemiological study of keratoconus: Evidence for major gene determination

Keratoconus (KC) is a noninflammatory corneal thinning disorder and the maj or cause of cornea transplantation in the Western world. Genetic factors ha ve been suggested in the cause of KC, We conducted a family study to invest igate genetic contributions to the development of KC by evaluating familial aggregation and testing genetic models with segregation analysis. KC was d iagnosed based on clinical criteria. Familial aggregation of KC was evaluat ed using both clinical status and three videokeratography indices generated by the Topographic Modeling System (TMS-1), The estimated KC prevalence in first-degree relatives was 3.34% (41/1,226, 95% CI: 3.22-3.46%), which is 15 to 67 times higher than that in the general population (0.23-0.05%). For all three videokeratography indices, CK, IS, and KISA, KC propositi had si gnificantly higher mean values than controls (all P < 0.0001), Clinically u naffected parents also had significantly higher values for these indices th an controls (all P < 0.016), The correlation of KISA in sib and parent-offs pring pairs (r = 0.30 and 0.22, respectively, both P < 0.0005) was signific antly greater than that in marital pairs (r = 0.14), and the latter was not significantly different from zero. We performed segregation analysis on KI SA in 95 families ascertained through KC propositi, Hypotheses of both spor adic and environmental models were rejected (P < 0.001); a major gene model was not rejected (P > 0.1), Additionally, the most parsimonious model was autosomal recessive. In conclusion, we observed strong evidence of familial aggregation in KC and its subclinical indices and this aggregation is like ly due to a major gene effect. (C) 2000 Wiley-Liss, Inc.