Novel Isoniazid- and Ethionamide-resistance loci in mycobacterium tuberculosis identified by phenome-wide association scans

Due to the wide spread of multidrug-resistant tuberculosis, Mycobacterium tuberculosis (MTB) has once again become a serious public health threat. However, drug resistance mechanisms and the many loci related to drug resistance in MTB currently remain unclear. Similar to genome-wide association studies (GWASs), phenome-wide association scans (PheWAS) is a method for evaluating the association between whole phenotypes and a significant SNP. In this study, we identified S315N, S315T and R463L SNP sites within the katG gene that are related to INH-resistance as well as W191R and G169S SNPs within the katG gene related to ETH-resistance in MTB using the PheWAS method with the available data of Zhang et al. Compared with the GWAS results reported by Zhang et al., R463L and S315N were new sites of the INH prodrug identified by the PheWAS method. Moreover, S266R on gene ethA and A187V variation on mshA are also new sites that were found to be significantly associated with the resistance of ETH by our approach. The loci found by the PheWAS analysis method in this study had been experimentally estimated to be associated with drug resistance in MTB. These findings lend further credence to our PheWAS analysis method in SNP analysis and demonstrate the power of PheWAS in genetic disease loci identification.