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

Authors

Shicheng Guo, Marshfield Clinic Research Institute
Shuai Jiang, Fudan University
Narendranath Epperla, The Ohio State University
Yanyun Ma, Fudan University
Mehdi Maadooliat, Marquette UniversityFollow
Zhan Ye, Marshfield Clinic Research InstituteFollow
Brent Olson, Marshfield Clinic Research Institute
Minghua Wang, Soochow University
Terrie Kitchner, Marshfield Clinic Research Institute
Jeffrey Joyce, Marshfield Clinic Research Institute
Peng An, China Agricultural University
Fudi Wang, Zhejiang University School of Medicine
Robert Strenn, Marshfield Clinic Research Institute
Joseph J. Mazza, Marshfield Clinic Research Institute
Jennifer K. Meece, Marshfield Clinic Research Institute
Wenyu Wu, Fudan University
Li Jin, Fudan University
Judith A. Smith, University of Wisconsin
Jiucan Wang, Fudan University
Steven J. Schrodi, Marshfield Clinic Research InstituteFollow

Document Type

Article

Language

eng

Publication Date

4-25-2019

Publisher

American Society of Hematology

Source Publication

Blood

Source ISSN

0006-4971

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 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.

Comments

Accepted version. Blood, Vol. 133, No. 17 (April 25 2019) : 1888-1898. DOI. © 2019 American Society of Hematology. Used with permission.

Mehdi Maadooliat was also affiliated with Marshfield Clinic Research Institute at the time of publication.

Recommended Citation

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.
https://epublications.marquette.edu/math_fac/4