Secondary Phenotype Analysis in Ascertained Family Studies

• Activity Number: 359
• Type: Contributed
• Date/Time: Tuesday, August 11, 2015 : 10:30 AM to 12:20 PM
• Sponsor: Section on Statistics in Epidemiology
• Author(s): Roula Tsonaka* and Renaud Tissier and Jeanine Houwing-Duistermaat
• Companies: Leiden University Medical Center and Leiden University Medical Center and Leiden University Medical Center
• Keywords: Multivariate Probit model ; Mixed models ; Heritability

Abstract

Genetic studies typically adopt a case-control design to test associations between the case-control status and genetic variants. In addition to this primary phenotype a number of additional traits, known as secondary phenotypes, are routinely recorded e.g. metabolomics, transcriptomics, etc. Studying associations between genetic variants and these traits is of great interest. However, failure to properly adjust for the sampling design may lead to biased estimates. Several methods have been proposed, but they are limited to case-control studies and not directly applicable to more complex designs, such as the multiple-cases families. A proper secondary phenotype analysis in this case is complicated by the often complex sampling design, the familial correlations and the mixed-type phenotypes. We propose a novel approach which pairs methods for mixed-effects models with the retrospective likelihood. Simulations showed that ignoring the sampling mechanism can lead to false positives and severe underestimation of the heritability for secondary phenotypes. Finally we exemplified our method in the analysis of the Leiden Longevity study, a multiple-cases family study for healthy ageing.