Thrombosis is a complex trait with both genetic and environmental components.¹ In general, disease status is a qualitative trait where individuals are diagnosed as affected or unaffected, but it is now accepted that underlying the disease there is a continuum trait termed liability, susceptibility, or risk. Liability cannot be measured directly, but it can be modelled and estimated. Disease results when an individual’s liability is above a critical value or threshold, whereas liability values below the threshold correspond to healthy individuals. These threshold models of an underlying continuous scale of risk allow inferences that are compatible with current models of gene action.²

Quantitative plasma phenotypes, such as those related to haemostasis, are also complex traits, whose regulation depends on multiple genetic and environmental factors.³ Classical statistical methods are unable to quantify or partition the genetic and environmental factors determining the variability in such complex traits. However, variance component methods have been developed which allow the examination of sources of correlation between quantitative physiological measures and disease outcomes.⁴ These statistical genetic methods also permit the localisation and evaluation of the relative effects of the genes involved.⁵

We have applied these methods to the Genetic Analysis of Idiopathic Thrombophilia Project (GAIT Project) to characterise the genetic determinants responsible for idiopathic thrombophilia. Using a family based approach, we estimated that idiopathic thrombophilia has a heritability of 0.61, indicating that 61% of variation in liability to thrombosis at the population level can be attributed to genetic factors.⁶ Phenotypic correlations were also evaluated between 27 plasma phenotypes related to haemostasis and thrombosis liability.⁶ It was found that genetic factors were mainly responsible for these phenotypic correlations,⁶ indicating that some of the genes that regulate quantitative variation in these plasma phenotypes also affect the risk of thrombosis. These …