Refining multivariate disease phenotypes for high chip heritability

Abstract

Background: Statistical genetics shows that the success of both genetic association studies and genomic prediction methods is positively associated with the heritability of the trait used in the analysis. Identifying highly heritable components of a complex disease can thus enhance genetic studies of the disease. Existing heritable component analysis methods use data from related individuals to compute linearly-combined traits to maximize heritability. Recent advances in acquiring genome-wide markers have enhanced heritability estimation using genotypic data from apparently unrelated individuals, which is referred to as the chip heritability. Novel statistical models are thus needed to identify disease components (subtypes) with high chip heritability. Methods: We propose an optimization approach to identify highly heritable components of a complex disease as a function of multiple clinical variables. The heritability of the components is estimated directly from unrelated individuals using their genome-wide single nucleotide polymorphisms. The proposed approach can also model the fixed effects due to covariates, such as age and race, so that the derived traits have high chip heritability after correcting for fixed effects. A new sequential quadratic programming algorithm is developed to efficiently solve the proposed optimization problem. Results: The proposed algorithm was validated both in simulations and the analysis of a real-world dataset that was aggregated from genetic studies of cocaine, opoid, and alcohol dependence. Simulation studies demonstrated that the proposed approach could identify the hypothesized component from multiple synthesized features. A case study on cocaine dependence (CD) identified a quantitative trait that achieved chip heritability of 0.86 estimated using a cross-validation process. This quantitative trait corresponded to the likelihood of an individual's membership in a CD subtype. Clinical analysis showed that the subtype enclosed individuals who reported heavy use of cocaine but few withdrawal symptoms. Conclusions: Extensive experiments on both synthetic and real-world data demonstrate the effectiveness of the proposed approach as a means to find meaningful disease components with high chip heritability.