Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis
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Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis. / Tan, Qihua; B Hjelmborg, Jacob V; Thomassen, Mads; Jensen, Andreas Emil Kryger; Christiansen, Lene; Christensen, Kaare; Zhao, Jing Hua; Kruse, Torben A.
In: B M C Proceedings, Vol. 8, No. Suppl 1, S82, 2014, p. 1-6.Research output: Contribution to journal › Conference article › Research › peer-review
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TY - GEN
T1 - Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis
AU - Tan, Qihua
AU - B Hjelmborg, Jacob V
AU - Thomassen, Mads
AU - Jensen, Andreas Emil Kryger
AU - Christiansen, Lene
AU - Christensen, Kaare
AU - Zhao, Jing Hua
AU - Kruse, Torben A
PY - 2014
Y1 - 2014
N2 - Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees, which could affect statistical assessment of the genetic effects. Approaches have been proposed to integrate kinship correlation into the mixed-effect models to explicitly model the genetic relationship. These have proved to be an efficient way of dealing with sample clustering in pedigree data. Although current algorithms implemented in popular statistical packages are useful for adjusting relatedness in the mixed modeling of genetic effects on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2-level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change of a phenotype, integrating kinship correlation in the analysis. We apply our method to the Genetic Analysis Workshop 18 genome-wide association studies data on chromosome 3 to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees. Our method identifies genetic variants associated with blood pressure with estimated inflation factors of 0.99, suggesting that our modeling of random effects efficiently handles the genetic relatedness in pedigrees. Application to simulated data captures important variants specified in the simulation. Our results show that the method is useful for genetic association studies in related samples using longitudinal design.
AB - Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees, which could affect statistical assessment of the genetic effects. Approaches have been proposed to integrate kinship correlation into the mixed-effect models to explicitly model the genetic relationship. These have proved to be an efficient way of dealing with sample clustering in pedigree data. Although current algorithms implemented in popular statistical packages are useful for adjusting relatedness in the mixed modeling of genetic effects on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2-level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change of a phenotype, integrating kinship correlation in the analysis. We apply our method to the Genetic Analysis Workshop 18 genome-wide association studies data on chromosome 3 to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees. Our method identifies genetic variants associated with blood pressure with estimated inflation factors of 0.99, suggesting that our modeling of random effects efficiently handles the genetic relatedness in pedigrees. Application to simulated data captures important variants specified in the simulation. Our results show that the method is useful for genetic association studies in related samples using longitudinal design.
U2 - 10.1186/1753-6561-8-S1-S82
DO - 10.1186/1753-6561-8-S1-S82
M3 - Conference article
C2 - 25519411
VL - 8
SP - 1
EP - 6
JO - B M C Proceedings
JF - B M C Proceedings
SN - 1753-6561
IS - Suppl 1
M1 - S82
ER -
ID: 138354450