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

Author:

Guo Shicheng1ORCID,Jiang Shuai23ORCID,Epperla Narendranath4ORCID,Ma Yanyun23ORCID,Maadooliat Mehdi15ORCID,Ye Zhan6ORCID,Olson Brent6,Wang Minghua7ORCID,Kitchner Terrie1,Joyce Jeffrey1,An Peng8,Wang Fudi9,Strenn Robert6,Mazza Joseph J.10,Meece Jennifer K.11,Wu Wenyu12,Jin Li23,Smith Judith A.13,Wang Jiucun2314ORCID,Schrodi Steven J.115ORCID

Affiliation:

1. Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, WI;

2. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and

3. Human Phenome Institute, Fudan University, Shanghai, China;

4. Division of Hematology, The Ohio State University, Columbus, OH;

5. Department of Mathematics, Statistics and Computer Science, Marquette University, Milwaukee, WI;

6. Biomedical Informatics Research Center, Marshfield Clinic Research Institute, Marshfield, WI;

7. Department of Biochemistry and Molecular Biology, Medical College, Soochow University, Suzhou, China;

8. Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China;

9. Nutrition Discovery Innovation Center, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China;

10. Clinical Research Center and

11. Integrated Research and Development Laboratory, Marshfield Clinic Research Institute, Marshfield, WI;

12. Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China;

13. Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI;

14. Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China; and

15. Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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