Genetic epidemiological study of keratoconus: evidence for major gene determination

Keratoconus (KC) is a noninflammatory corneal thinning disorder and the major cause of cornea transplantation in the Western world. Genetic factors have been suggested in the cause of KC. We conducted a family study to investigate genetic contributions to the development of KC by evaluating familial aggregation and testing genetic models with segregation analysis. KC was diagnosed based on clinical criteria. Familial aggregation of KC was evaluated 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 significantly higher mean values than controls (all P < 0.0001). Clinically unaffected parents also had significantly higher values for these indices than controls (all P < 0.016). The correlation of KISA in sib and parent-offspring pairs (r = 0.30 and 0.22, respectively, both P < 0.0005) was significantly greater than that in marital pairs (r = 0.14), and the latter was not significantly different from zero. We performed segregation analysis on KISA in 95 families ascertained through KC propositi. Hypotheses of both sporadic 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 likely due to a major gene effect.