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

Blood
Shicheng GuoSteven J Schrodi

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.

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Citations

Sep 1, 2019·Medicinal Research Reviews·Zhong-Ming Qian, Ya Ke
Sep 4, 2020·Signal Transduction and Targeted Therapy·Yangli XieLin Chen
Dec 27, 2019·Current Opinion in Anaesthesiology·Thomas B BartnikasCaroline A Enns
Jan 31, 2021·International Journal of Molecular Sciences·Sara PelucchiAlberto Piperno
Mar 4, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Tatjana Seitz, Claus Hellerbrand

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