Results showed no evidence of a departure from Hardy-Weinberg equilibrium (HWE) for any of the SNPs (all P>0.05). Linkage disequilibrium (LD) between SNPs is summarized in Figure 1, showing moderate to strong LD between several SNCA SNPs, with many r2 values of 0.30 or greater. The proportion of carriers of the minor allele in controls is displayed in Table 1 for seven different age categories: <60 years, 60-69 years, 70-74 years, 75-79 years, 80-84 years, 85-89 years, and ≥90 years. These age categories were chosen to display trends while maximizing the number of controls in each category. As shown in Table 1, there was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P=0.021). Results were similar for rs3775439, which was in strong LD with rs10014396 (r2 = 0.84); the proportion of carriers of the minor allele decreased from 32% in controls younger than 60 to 19% in those 90 or older (P=0.025). For the remaining SNCA SNPs, the proportion of carriers of the minor allele did not noticeably increase or decrease as age increased in controls (all P>0.19).

The healthy control series was supplemented with 426 PD cases seen at Mayo Clinic Florida to examine associations of SNCA SNPs with PD [21]. The mean age of PD cases was 72±6.11 SD years (range: 30-92 years), mean age at PD onset was 62±6.12 SD years (range: 26-85 years), and 233 (55%) were male. All PD cases were white and of European ancestry, examined and observed longitudinally by a neurologist, and diagnosed with PD according to published criteria [22]. There were no known related samples within or between the diagnosis groups. All subjects self-identified their ethnicity.

Table 2 presents single SNP associations with PD. Of particular interest, rs10014396 and rs3775439, both associated with survival without neurological disease in controls, were not associated with PD (ORs 0.92 & 0.95, P>0.58). Significant protective associations were observed for rs1372519 (OR: 0.76, P=0.034) and rs1372520 (OR: 0.76, P=0.039). For the remaining SNCA SNPs, a number of significant risk associations with PD were observed, including rs356218, rs2736990, rs2572324, rs2737033, rs2583959, rs2737012, rs2619361, rs2619362, rs2619363, and rs2583988 (ORs between 1.39 and 1.64, all P<0.026), all of which were in moderate to strong LD (Figure 1).

In this exploratory study involving more than 750 controls free of neurological disease, the findings suggest that SNCA may play a part in determining whether or not a given individual ages successfully as measured by the specific outcome of survival without neurological disease. For two SNCA SNPs, rs10014396 and rs3775439, the minor allele was less common in older controls. The lower proportion of carriers of the minor allele for these two SNPs in the older controls suggests that unobserved individuals who are carriers of these alleles experience death or neurological disease at an earlier age and are therefore removed from the pool of controls free of neurological disease at later ages, indicating that the presence of these alleles increases the risk of neurological disease or death. Although not of primary interest in this study, significant associations of SNCA SNPs with PD were observed in this study and previous studies [15-19,21]. Protective effects were observed for rs13752519 and rs1372520. 

Genetic analysis involved extracting DNA from0.76 (0.58, 0.98) 0.034 90757394 rs3756063 G 442 (52%) 738 (48%) 1.30 (0.97, 1.74) 0.075 90757505 rs1372520 T 155 (18%) 338 (22%) 0.76 (0.59, 0.99) 0.039 90757735 rs2619361 A 287 (34%) 400 (26%) 1.61 (1.26, 2.06), p<0.001 90757845 rs2619362 T 94 (28%) 66 (23%) 1.61 (1.26, 2.07), p<0.001 90758389 rs2301135 G 436 (53%) 721 (49%) 1.24 (0.92, 1.68) p=0.15 90759047 rs2619363 T 286 (34%) 400 (26%) 1.59 (1.24,2.04), p<0.001; and at rs2583988 T with OR=1.56(95%CI:1.22-2.01), p<0.001.
PD refers to Parkinson's disease while SNP refers to single nucleotide polymorphism, MA to minor allele, OR to odds ratio and CI to confidence interval.
*Chromosomal positions refer to February2009(GRCH37/hg19) genome assembly [SNCA is located at Chr4;90,645,25190,759,447]. Odds ratios(ORs),95% confidence intervals(CIs) and p-values were obtained through logistic regression adjusted for age and gender and correspond to presence versus absence of the minor allele.

Neurological disease is relatively rare, and therefore the possibility of a Type II error (i.e. a false negative association), particularly after adjustment for multiple testing, is important to consider. Larger series of healthy controls, in particular healthy nonagenarians and centenarians, are needed in future evaluations of SNCA's role in the aging process. Finally, an important caveat of genetic aging studies is the possibility of population stratification given migration patterns and generational differences in lifestyle. Risk effects were noted for a number of other SNPs that were also in relatively high LD with each other. In addition to their known role in PD, SNCA variants have also been implicated in both diffuse Lewy body disease [30] and multiple system atrophy [31,32,33]. The associations between SNCA variants and survival without neurological disease observed in this study provide additional support for all of these findings and also further underscore the pleiotropic nature of SNCA.

Acknowledging these limitations, our results indicate that in addition to its known role in PD and a-synucleinopathies, SNCA may influence the likelihood of survival without neurological disease. Our findings require validation in an independent series, but suggest that further study of the role of SNCA variation in aging and cognitive function is warranted.