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A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron metabolism gene

Shicheng Guo, Shuai Jiang, Narendranath Epperla, Yanyun Ma, Mehdi Maadooliat, Zhan Ye, Brent Olson, Minghua Wang, Terrie Kitchner, Jeffrey Joyce, Robert Strenn, Joseph J. Mazza, Jennifer K. Meece, Wenyu Wu, Li Jin, Judith A. Smith, Jiucun Wang and Steven J. Schrodi

Key points

  • An exome scan for recessive effects reveals FGF6 as a hemochromatosis susceptibility gene.

  • FGF-6 decreases ferrous iron uptake in liver cells and induces increased hepcidin expression.

Abstract

Standard analyses applied to genome-wide association data are well-designed to detect additive effects of moderate strength. However, the power for standard 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 FGF-6 regulates iron homeostasis and induces transcriptional regulation of hepcidin. Moreover, specific identified FGF6 variants 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.

  • Submitted October 10, 2018.
  • Accepted February 20, 2019.