We did not find evidence for a significant association between the UCHL1
S18Y polymorphism and PD risk or AAO in a well-characterized sample of white individuals. Two major strengths of this study were the large sample size and the fact that NGRC subjects were collected using uniform ascertainment strategies, clinical diagnostic criteria, and data collection procedures to minimize heterogeneity across sites. A potential limitation of our work was that sex ratio and recruitment site distribution differed for cases and controls (), which might have biased our findings. However, adjustment for sex and site had little impact on our results. Further, we did not observe a significant association with PD risk after stratification by sex or site. Our results might also be biased by population stratification [25
]; however, the magnitude of such confounding by genetic ancestry is probably minimal for our study, because all of our subjects self-reported as white and UCHL1
S18Y allele frequencies show little variation across European and European-American control populations [5
]. Finally, because we used a candidate single nucleotide polymorphism (SNP) approach rather than a gene-wide tagSNP approach [26
], we cannot rule out the possibility that there are other variants in UCHL1
that are associated with PD.
A large number of studies have examined the association between the UCHL1
S18Y variant and PD risk, with conflicting results [7
]. With the exception of the case–control analysis by Healy et al.
], the sample size of these studies has been substantially smaller than our study. Data from most of these studies have been included in two partially overlapping meta-analyses which arrived at different conclusions [16
]. The first meta-analysis by Maraganore et al.
] combined data on 1970 cases and 2224 controls from seven white and four Asian studies and provided evidence in favor of UCHL1
as a PD susceptibility gene. An association between reduced risk of PD and the Y variant was seen under both dominant (OR, 0.84; 95% CI, 0.73–0.95) and recessive (OR, 0.71; 95% CI, 0.57–0.88) models. The meta-analysis was significant when restricted to younger (≤67 years) cases and controls (dominant model OR, 0.73; 95% CI, 0.59–0.89) but not older cases and controls (dominant model OR, 0.96; 95% CI, 0.78–1.18) and a significant association was seen for the meta-analysis restricted to studies of Asian subjects, but not for white subjects [16
]. The last observation is intriguing and raises the possibility that S18Y either (i) modifies PD risk, but only when combined with other genetic or environmental factors that are more prevalent in Asian than white populations or (ii) does not modify PD risk, but is in strong linkage disequilibrium (LD) with a true risk variant(s) in Asians but not in whites, potentially arising from different LD patterns between these ethnic groups. An alternative explanation is that case–control studies conducted in Asian populations have a higher power to consistently detect weak effects because they have a higher frequency of the Y variant.
In the second meta-analysis, Healy et al.
] combined original data on 1536 cases and 1487 controls of Northern European ancestry with data from seven existing studies on white subjects. The authors did not observe an association between UCHL1
S18Y and PD in either their case–control sample alone (dominant model OR, 1.06; 95% CI, 0.91–1.25; recessive model OR, 1.47; 95% CI, 0.95–2.27) or in the overall meta-analysis of 6,594 white subjects (dominant model OR, 0.96; 95% CI, 0.86–1.08; recessive model OR, 1.01; 95% CI, 0.76–1.35) [18
]. The authors also used a tagSNP approach [26
] to identify two additional SNPs that, in conjunction with S18Y, captured much of the common variation across the UCHL1
]. They did not observe evidence for an association between PD risk and any of the tagSNPs, either analyzed individually or together as three locus haplotypes [18
Two small case–control studies have been published subsequent to the two meta-analyses. One examined 335 cases and 341 controls who were ethnic Chinese from Singapore [19
], and the other examined 296 cases and 285 controls from Sweden [20
]. Both studies reported an inverse association between the Y variant and PD when comparing younger cases to younger controls, but no association between the Y variant and PD for older cases and controls [19
]. This is consistent with the age-stratified meta-analysis by Maraganore et al.
] and with the trends seen in our analyses of mean AAO and of risk-stratified by ABD. The Swedish study also reported a significant association for the combined sample; however, the results were only significant for a one-sided test (one-sided P
-value for the association between Y allele and PD was 0.049) [20
]. The positive findings in younger subjects in these two studies should be interpreted with caution, given the small sample sizes in the subgroup analysis.
Despite the large sample used in our study, we cannot rule out the possibility that UCHL1
S18Y exerts a weak protective effect on PD risk in white subjects. Although not statistically significant, our estimates of the OR for Y/S heterozygotes and Y/Y homozygotes compared with S/S homozygotes were less than 1, and this trend was more prominent when we restricted our analysis to cases and controls with ABD ≤67 years of age (). We were underpowered to detect weak effects of the UCHL1
S18Y variant, particularly in our age-stratified analysis. As previously noted [18
], a sample size of over 13200 is needed to have 80% power to detect an OR of 0.90 at level 0.05 under a dominant model of inheritance and even larger samples are needed for a recessive model [18
]. Because of these sample size requirements, additional large studies and meta-analysis will be needed to confirm or rule out the possibility that the S18Y polymorphism has a weak effect on PD susceptibility. Our results, along with those of previous studies [16
], suggest that such work might benefit from including either age-stratified analysis or restriction to younger cases and controls. Synthesis across studies is aided by resources such as the PDGene database (http://www.pdgene.org
). This online, publicly available, resource has a comprehensive summary of published PD genetic association studies. The current meta-analysis results on PDGene, combining data on 4395 cases and 4598 controls from 15 studies, shows a significant association between the Y variant and reduced PD risk for all studies, but not when restricted to white subjects.
Our data contribute to a growing line of evidence that UCHL1 S18Y is not strongly associated with risk of late-onset PD in white individuals. However, the role of this polymorphism in determining PD risk in younger individuals and in non-white populations is less clear and merits further study.