Fibroblast Growth Factor 20 Polymorphisms and Haplotypes Strongly Influence Risk of Parkinson Disease

Duke University, Durham, North Carolina, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 07/2004; 74(6):1121-7. DOI: 10.1086/421052
Source: PubMed


The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.

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    • "Given that FGFs were classified together purely on a structural basis [1] the diversity in their biological functions and modes of action is not surprising. To date, FGFs have been shown to regulate a myriad of fundamental processes such as cell differentiation, proliferation , morphogenesis and metabolism while aberrant FGF signaling has been linked to pathological conditions of cancer and metabolic disease [1] [2] [3] [4] [5] [6]. "
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    • "To reach power to detect these association signals with genome-wide significance, they combined data from their discovery and follow-up stages, and attempted to replicate their findings in the independent study sample of 23andMe [17]. In this combined analysis, four new loci reached genome-wide significance the strongest candidate at these loci are STX1B, FGF20 (which was previously reported in a candidate-gene study performed in a large family [34]), STBD1, and GPNMB. They also were the first to report a genome-wide significant association to the PARK16 locus in Europeans. "
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    • "Fgf20, a paracrine Fgf, with neurotrophic activity in cultured dopaminergic neurons (Ohmachi et al., 2000, 2003) has been suggested to play important roles in the development of dopaminergic neurons (Grothe et al., 2004; Takagi et al., 2005; Correia et al., 2007; Shimada et al., 2009). In addition, FGF20 mutations may result in Parkinson's disease (van der Walt et al., 2004; Satake et al., 2007; IPDGC, 2011; Pan et al., 2012; Pihlstrøm et al., 2013; Wang et al., 2013). As these findings indicate that FGF20 may provide useful clues on the etiology and therapy of Parkinson's disease, a succinct review on the roles of FGF20 in dopaminergic neurons and Parkinson's disease has been provided. "
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