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

Blood. 2019 Apr 25;133(17):1888-1898. doi: 10.1182/blood-2018-10-879585. Epub 2019 Feb 27.

Abstract

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Case-Control Studies
  • Diploidy
  • Exome / genetics*
  • Female
  • Fibroblast Growth Factor 6 / genetics*
  • Fibroblast Growth Factor 6 / metabolism
  • Follow-Up Studies
  • Gene Expression Regulation*
  • Genes, Recessive
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Hemochromatosis / genetics
  • Hemochromatosis / pathology*
  • Hepcidins / genetics
  • Hepcidins / metabolism*
  • Humans
  • Iron / metabolism*
  • Iron Overload / genetics
  • Iron Overload / pathology*
  • Male
  • Middle Aged
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein Interaction Maps
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / pathology
  • Sequence Homology

Substances

  • FGF6 protein, human
  • Fibroblast Growth Factor 6
  • HAMP protein, human
  • Hepcidins
  • Iron