Mixed model with correction for case-control ascertainment increases association power

Hayeck T, Zaitlen N, Loh PR, Vilhjalmsson B, Pollack S, Gusev A, Yang J, Chen GB, Goddard M, Visscher P, Patterson N, Price A. Mixed model with correction for case-control ascertainment increases association power. Am J Hum Genet. 2015;96(5):720–30.

Abstract

We introduce a liability-threshold mixed linear model (LTMLM) association statistic for case-control studies and show that it has a well-controlled false-positive rate and more power than existing mixed-model methods for diseases with low prevalence. Existing mixed-model methods suffer a loss in power under case-control ascertainment, but no solution has been proposed. Here, we solve this problem by using a χ(2) score statistic computed from posterior mean liabilities (PMLs) under the liability-threshold model. Each individual's PML is conditional not only on that individual's case-control status but also on every individual's case-control status and the genetic relationship matrix (GRM) obtained from the data. The PMLs are estimated with a multivariate Gibbs sampler; the liability-scale phenotypic covariance matrix is based on the GRM, and a heritability parameter is estimated via Haseman-Elston regression on case-control phenotypes and then transformed to the liability scale. In simulations of unrelated individuals, the LTMLM statistic was correctly calibrated and achieved higher power than existing mixed-model methods for diseases with low prevalence, and the magnitude of the improvement depended on sample size and severity of case-control ascertainment. In a Wellcome Trust Case Control Consortium 2 multiple sclerosis dataset with >10,000 samples, LTMLM was correctly calibrated and attained a 4.3% improvement (p = 0.005) in χ(2) statistics over existing mixed-model methods at 75 known associated SNPs, consistent with simulations. Larger increases in power are expected at larger sample sizes. In conclusion, case-control studies of diseases with low prevalence can achieve power higher than that in existing mixed-model methods.
Last updated on 03/06/2023