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Family aggregation and distribution of videokeratography parameters were examined. Segregation of <jats:italic>KSI<\/jats:italic>,<jats:italic> KISA<\/jats:italic> and <jats:italic>6mm Fourier asymmetry<\/jats:italic> alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non\u2010mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3\u201311.9) based on <jats:italic>KISA<\/jats:italic> index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non\u2010KC family members as well as normal controls (<jats:sc>anova<\/jats:sc> p\u00a0&lt;\u00a00.001). Hypotheses accepted as most parsimonius models of inheritance (p\u00a0&gt;\u00a00.1) for all indices indicated the presence of a non\u2010mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non\u2010mendelian major gene effect. Low genotype\u2010phenotype 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\u2010familial keratoconus.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aos.12389","type":"journal-article","created":{"date-parts":[[2014,3,17]],"date-time":"2014-03-17T02:40:54Z","timestamp":1395024054000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Segregation analysis suggests that keratoconus is a complex non\u2010mendelian disease"],"prefix":"10.1111","volume":"92","author":[{"given":"\u00c1gnes","family":"Kriszt","sequence":"first","affiliation":[{"name":"Department of Ophthalmology University of Debrecen Medical and Health Science Center Debrecen Hungary"},{"name":"Department of Biophysics and Cell Biology University of Debrecen Medical and Health Science Center Debrecen 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