Improved detection of genetic loci in estimated glomerular filtration rate and type 2 diabetes using a pleiotropic cFDR method

摘要

Genome-wide association studies (GWAS) have been shown to have the potential of explaining more of the “missing heritability” of complex human phenotypes by improving statistical approaches. Here, we applied a genetic-pleiotropy-informed conditional false discovery rate (cFDR) to capture additional polygenic effects associated with estimated glomerular filtration rate (creatinine) (eGFRcrea) and type 2 diabetes (T2D). The cFDR analysis improves the identification of pleiotropic variants by incorporating potentially shared genetic mechanisms between two related traits. The Q–Q and fold-enrichment plots were used to assess the enrichment of SNPs associated with eGFRcrea or T2D, and Manhattan plots were used for showing chromosomal locations of the significant loci detected. By applying the cFDR method, we newly identified 74 loci for eGFRcrea and 3 loci for T2D with the cFDR criterion of 0.05 compared with previous related GWAS studies. Four shared SNPs were detected to be associated with both eGFRcrea and T2D at the significant conjunction cFDR level of 0.05, and these shared SNPs had not been reported in previous studies. In addition, we used DAVID analysis to perform functional analysis of the shared SNPs’ annotated genes and found their potential hidden associations with eGFRcrea and T2D. In this study, the cFDR method shows the feasibility to detect more genetic variants underlying the heritability of eGFRcrea and T2D, and the overlapping SNPs identified could be regarded as candidate loci that provide a thread of genetic mechanisms between eGFRcrea and T2D in future research.