title: Segregation analysis suggests that keratoconus is a complex non-mendelian disease.
abstract: OBJECTIVE
  Complex segregation analysis of 60 unrelated sporadic keratoconus (KC) families was performed to reveal the presumed mode of inheritance in our dataset.
  
  
  METHODS
  Sixty probands, 212 family members and 212 age and gender matched healthy controls underwent clinical and videokeratographic examination. Family aggregation and distribution of videokeratography parameters were examined. Segregation of KSI, KISA and 6mm Fourier asymmetry alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non-mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package.
  
  
  RESULTS
  In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3-11.9) based on KISA index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non-KC family members as well as normal controls (anova p < 0.001). Hypotheses accepted as most parsimonius models of inheritance (p > 0.1) for all indices indicated the presence of a non-mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected.
  
  
  CONCLUSIONS
  Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non-mendelian major gene effect. Low genotype-phenotype correlation in sporadic KC families can make linkage studies difficult, thus genome wide association studies, epigenetic and pathway analyses may provide more information on disease pathogenesis in non-familial keratoconus.
authors.affiliation: Department of Ophthalmology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary; Department of Biophysics and Cell Biology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Kriszt
authors.forename: Gergely
authors.initials: G
authors.lastname: Losonczy
authors.forename: András
authors.initials: A
authors.lastname: Berta
authors.forename: György
authors.initials: G
authors.lastname: Vereb
authors.forename: Lili
authors.initials: L
authors.lastname: Takács
mesh_terms: D000328:Adult; D020090:Chromosome Segregation / Q000235:genetics*; D019781:Corneal Topography; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D040582:Inheritance Patterns; D007640:Keratoconus / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D055815:Young Adult
keywords: complex segregation analysis; complex, non-mendelian disease; familial aggregation; forme fruste; keratoconus; non-mendelian major gene; videokeratographic indices