Apr 5, 2016

Mixed Model Association with Family-Biased Case-Control Ascertainment

BioRxiv : the Preprint Server for Biology
tristan hayeckAlkes Price

Abstract

Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where cases and controls are ascertained non-randomly with respect to family relatedness. Previous work has shown that this type of ascertainment can severely bias heritability estimates; we show here that it also impacts mixed model association statistics. We introduce a family-based association statistic (LT-Fam) that is robust to this problem. Similar to LTMLM, LT-Fam is computed from posterior mean liabilities (PML) under a liability threshold model; however, LT-Fam uses published narrow-sense heritability estimates to avoid the problem of biased heritability estimation, enabling correct calibration. In simulations with family-biased case-control ascertainment, LT-Fam was correctly calibrated (average χ2 = 1.00), whereas Armitage Trend Test (ATT) and standard mixed model association (MLM) were mis-...Continue Reading

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Mentioned in this Paper

Diabetes Mellitus, Non-Insulin-Dependent
Study
Myocardial Infarction
Genetic Association Studies
Familial Atypical Mole Melanoma Syndrome
Dorsal
Simulation
Posterior Pituitary Disease
Cohort
Atypical Teratoid/Rhabdoid Tumor

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