Genome-wide mapping of quantitative trait loci in admixed populations using mixed linear model and Bayesian multiple regression analysis

Ali Toosi, Rohan L. Fernando, Jack C. M. Dekkers

Population stratification and cryptic relationships have been the main sources of excessive false-positives and false-negatives in population-based association studies. Many methods have been developed to model these confounding factors and minimize their impact on the results of genome-wide association studies. In most of these methods, a two-stage approach is applied where: (1) methods are used to determine if there is a population structure in the sample dataset and (2) the effects of population structure are corrected either by modeling it or by running a separate analysis within each sub-population. The objective of this study was to evaluate the impact of population structure on the accuracy and power of genome-wide association studies using a Bayesian multiple regression method. We conducted a genome-wide association study in a stochastically simulated admixed population. The genome was composed of six chromosomes, each with 1000 markers. Fifteen segregating quantitative trait loci contributed to the genetic variation of a quantitative trait with heritability of 0.30. The impact of genetic relationships and breed composition (BC) on three analysis methods were evaluated: single marker simple regression (SMR), single marker mixed linear model (MLM) and Bayesian multiple-regression analysis (BMR). Each method was fitted with and without BC. Accuracy, power, false-positive rate and the positive predictive value of each method were calculated and used for comparison. SMR and BMR, both without BC, were ranked as the worst and the best performing approaches, respectively. Our results showed that, while explicit modeling of genetic relationships and BC is essential for models SMR and MLM, BMR can disregard them and yet result in a higher power without compromising its false-positive rate. This study showed that the Bayesian multiple-regression analysis is robust to population structure and to relationships among study subjects and performs better than a single marker mixed linear model approach.