American Society of Hematology
Standard analyses applied to genome-wide association data are well designed to detect additive effects of moderate strength. However, the power for standard genome-wide association study (GWAS) analyses to identify effects from recessive diplotypes is not typically high. We proposed and conducted a gene-based compound heterozygosity test to reveal additional genes underlying complex diseases. With this approach applied to iron overload, a strong association signal was identified between the fibroblast growth factor–encoding gene, FGF6, and hemochromatosis in the central Wisconsin population. Functional validation showed that fibroblast growth factor 6 protein (FGF-6) regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6variants differentially impact iron metabolism. In addition, FGF6 downregulation correlated with iron-metabolism dysfunction in systemic sclerosis and cancer cells. Using the recessive diplotype approach revealed a novel susceptibility hemochromatosis gene and has extended our understanding of the mechanisms involved in iron metabolism.
Guo, Shicheng; Jiang, Shuai; Epperla, Narendranath; Ma, Yanyun; Maadooliat, Mehdi; Ye, Zhan; Olson, Brent; Wang, Minghua; Kitchner, Terrie; Joyce, Jeffrey; An, Peng; Wang, Fudi; Strenn, Robert; Mazza, Joseph J.; Meece, Jennifer K.; Wu, Wenyu; Jin, Li; Smith, Judith A.; Wang, Jiucan; and Schrodi, Steven J., "A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene" (2019). Mathematical and Statistical Science Faculty Research and Publications. 4.