A fast mrMLM algorithm for multi-locus genome-wide association studies

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Abstract

Abstract Background Recent developments in technology result in the generation of big data. In genome-wide association studies (GWAS), we can get tens of million SNPs that need to be tested for association with a trait of interest. Indeed, this poses a great computational challenge. There is a need for developing fast algorithms in GWAS methodologies. These algorithms must ensure high power in QTN detection, high accuracy in QTN estimation and low false positive rate. Results Here, we accelerated mrMLM algorithm by using GEMMA idea, matrix transformations and identities. The target functions and derivatives in vector/matrix forms for each marker scanning are transformed into some simple forms that are easy and efficient to evaluate during each optimization step. All potentially associated QTNs with P-values ≤ 0.01 are evaluated in a multi-locus model by LARS algorithm and/or EM-Empirical Bayes. We call the algorithm FASTmrMLM. Numerical simulation studies and real data analysis validated the FASTmrMLM. FASTmrMLM reduces the running time in mrMLM by more than 50%. FASTmrMLM also shows high statistical power in QTN detection, high accuracy in QTN estimation and low false positive rate as compared to GEMMA, FarmCPU and mrMLM. Real data analysis shows that FASTmrMLM was able to detect more previously reported genes than all the other methods: GEMMA/EMMA, FarmCPU and mrMLM. Conclusions FASTmrMLM is a fast and reliable algorithm in multi-locus GWAS and ensures high statistical power, high accuracy of estimates and low false positive rate. Author Summary The current developments in technology result in the generation of a vast amount of data. In genome-wide association studies, we can get tens of million markers that need to be tested for association with a trait of interest. Due to the computational challenge faced, we developed a fast algorithm for genome-wide association studies. Our approach is a two stage method. In the first step, we used matrix transformations and identities to quicken the testing of each random marker effect. The target functions and derivatives which are in vector/matrix forms for each marker scanning are transformed into some simple forms that are easy and efficient to evaluate during each optimization step. In the second step, we selected all potentially associated SNPs and evaluated them in a multi-locus model. From simulation studies, our algorithm significantly reduces the computing time. The new method also shows high statistical power in detecting significant markers, high accuracy in marker effect estimation and low false positive rate. We also used the new method to identify relevant genes in real data analysis. We recommend our approach as a fast and reliable method for carrying out a multi-locus genome-wide association study.

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