Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease.
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.
van der Walt
Joelle M
JM
Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Noureddine
Maher A
MA
Kittappa
Raja
R
Hauser
Michael A
MA
Scott
William K
WK
McKay
Ron
R
Zhang
Fengyu
F
Stajich
Jeffrey M
JM
Fujiwara
Kenichiro
K
Scott
Burton L
BL
Pericak-Vance
Margaret A
MA
Vance
Jeffery M
JM
Martin
Eden R
ER
D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012689:Sequence Homology, Nucleic Acid
C416003:FGF20 protein, human; D005346:Fibroblast Growth Factors; D004247:DNA