Wang et al.
propose a pathomechanism for FGF20
genetic association with PD via the over-expression of FGF20 and α-synuclein.4
They postulate a 3′UTR SNP (rs12720208) effects miRNA binding and results in the differential allele-specific expression of FGF20
, thereby altering FGF20 protein levels and consequently α-synuclein. This group first proposed FGF20
as a candidate PD gene as it was located under a linkage peak they identified in a study of small singleton and multiplex U.S. families.1-4
Subsequent studies have shown inconsistent results, positive only in one Japanese population,5
and negative in three Caucasian populations.6, 7
Likewise, the present study did not find any association between FGF20
genetic variability and risk of PD. In contrast to the original FGF20
study which used a pedigree-based analysis of familial and sporadic patients and controls,2, 4
replication studies, including ours, used an unrelated patient-control design; however, recent evidence suggests the genetic risks in sporadic PD may overlap with familial forms of the disease.12, 13
While the pedigree-based statistical method avoids bias from population stratification,2, 4, 14
cryptic relatedness may be negligible in outbred populations.15
Furthermore, in such populations, the classical patient-control association method may require similar or even smaller sample sizes than the pedigree-based test to assess genetic risk factors;16
therefore, differences in statistical approach are unlikely to account for our discrepant results.
Although we can not rule out an effect of SNP rs12720208 on miRNA binding, our functional study neither showed any association between the rs12720208 genotype and levels of FGF20 or α-synuclein, nor a relationship between the levels of FGF20 and α-synuclein. The considerable random variability between our nine post-mortem cases in both FGF20 and α-synuclein protein expression may help explain the differences observed in brain samples from only one patient of each rs12720208 genotype (n=3 in the original study).4
Our study does not support a significant role of FGF20 variability in PD risk, or a pathomechanism involving co-dependent FGF20 and α-synuclein protein levels. This study highlights the need for caution in interpreting association studies, even with functional data, before genetic findings have been adequately replicated.