Control for population structure and relatedness for binary traits in genetic association studies via logistic mixed models

H Chen, C Wang, MP Conomos, AM Stilp, Z Li… - The American Journal of …, 2016 - cell.com
H Chen, C Wang, MP Conomos, AM Stilp, Z Li, T Sofer, AA Szpiro, W Chen, JM Brehm
The American Journal of Human Genetics, 2016cell.com
Linear mixed models (LMMs) are widely used in genome-wide association studies (GWASs)
to account for population structure and relatedness, for both continuous and binary traits.
Motivated by the failure of LMMs to control type I errors in a GWAS of asthma, a binary trait,
we show that LMMs are generally inappropriate for analyzing binary traits when population
stratification leads to violation of the LMM's constant-residual variance assumption. To
overcome this problem, we develop a computationally efficient logistic mixed model …
Linear mixed models (LMMs) are widely used in genome-wide association studies (GWASs) to account for population structure and relatedness, for both continuous and binary traits. Motivated by the failure of LMMs to control type I errors in a GWAS of asthma, a binary trait, we show that LMMs are generally inappropriate for analyzing binary traits when population stratification leads to violation of the LMM's constant-residual variance assumption. To overcome this problem, we develop a computationally efficient logistic mixed model approach for genome-wide analysis of binary traits, the generalized linear mixed model association test (GMMAT). This approach fits a logistic mixed model once per GWAS and performs score tests under the null hypothesis of no association between a binary trait and individual genetic variants. We show in simulation studies and real data analysis that GMMAT effectively controls for population structure and relatedness when analyzing binary traits in a wide variety of study designs.
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