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On a Unifying ‘Reverse’ Regression for Robust Association Studies and Allele Frequency Estimation with Related Individuals

By Lin Zhang, Lei Sun

Posted 14 Nov 2018
bioRxiv DOI: 10.1101/470328

For genetic association studies with related individuals, standard linear mixed-effect model is the most popular approach. The model treats a complex trait (phenotype) as the response variable while a genetic variant (genotype) as a covariate. An alternative approach is to reverse the roles of phenotype and genotype. This class of tests includes quasi-likelihood based score tests. In this work, after reviewing these existing methods, we propose a general, unifying ‘reverse’ regression framework. We then show that the proposed method can also explicitly adjust for potential departure from Hardy–Weinberg equilibrium. Lastly, we demonstrate the additional flexibility of the proposed model on allele frequency estimation, as well as its connection with earlier work of best linear unbiased allele-frequency estimator. We conclude the paper with supporting evidence from simulation and application studies.

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