title: Combining information from linkage and association mapping for next-generation sequencing longitudinal family data.
abstract: In this analysis, we investigate the contributions that linkage-based methods, such as identical-by-descent mapping, can make to association mapping to identify rare variants in next-generation sequencing data. First, we identify regions in which cases share more segments identical-by-descent around a putative causal variant than do controls. Second, we use a two-stage mixed-effect model approach to summarize the single-nucleotide polymorphism data within each region and include them as covariates in the model for the phenotype. We assess the impact of linkage disequilibrium in determining identical-by-descent states between individuals by using markers with and without linkage disequilibrium for the first part and the impact of imputation in testing for association by using imputed genome-wide association studies or raw sequence markers for the second part. We apply the method to next-generation sequencing longitudinal family data from Genetic Association Workshop 18 and identify a significant region at chromosome 3: 40249244-41025167 (p-value = 2.3 × 10(-3)).
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Brunilda
authors.initials: B
authors.lastname: Balliu
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands ; Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Hae-Won
authors.initials: HW
authors.lastname: Uh
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Roula
authors.initials: R
authors.lastname: Tsonaka
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehringer
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands ; Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Quinta
authors.initials: Q
authors.lastname: Helmer
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat