A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene.
Shicheng GuoShuai JiangNarendranath EpperlaYanyun MaMehdi MaadooliatZhan YeBrent OlsonMinghua WangTerrie KitchnerJeffrey JoycePeng AnFudi WangRobert StrennJoseph J MazzaJennifer K MeeceWenyu WuLi JinJudith A SmithJiucun WangSteven J SchrodiPublished in: Blood (2019)
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.
Keyphrases
- copy number
- genome wide
- iron deficiency
- systemic sclerosis
- genome wide identification
- genome wide association study
- intellectual disability
- dna methylation
- interstitial lung disease
- computed tomography
- single cell
- magnetic resonance imaging
- rheumatoid arthritis
- genome wide association
- magnetic resonance
- autism spectrum disorder
- big data
- binding protein