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Figure 1. Linkage disequilibrium between SNPs in controls as measured by pairwise r2 values. Values are given as percentages out of maximum of 100. Solid black boxes indicate an r2 value of 100. doi:10.1371/journal.pone.0042877.g001

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).

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. The two age-associated SNCA SNPs were not among those that were associated with PD when supplementing the controls with the PD cases in disease-association analysis; this may be due to the different outcome measure used which relates not only to PD but to death and neurological disease in general.

Discussion

Similar to the results of our study, other studies have demonstrated associations between genes involved in neurodegen- erative disorders and successful aging outcomes. As described by Glatt et al. in their review of 29 different studies evaluating at least one other characteristic of healthy aging in addition to longevity [26], APOE, the known risk factor for Alzheimer’s disease, has been implicated in successful aging in several studies, however this association has not been consistently identified, and further study is therefore needed. Walter et al., in their genome-wide association study [27], identified evidence of association with survival free of major disease for GRIN2B, which has been implicated in Parkinson’s disease [28] and Alzheimer’s disease [29]. These findings, taken together with those from our study, suggest that the role of age-related neurodegenerative disease genes should be further studied in relation to healthy aging in general.

Lifespan in humans has been shown to display markable heritability, with estimates ranging between 20% and 30%, confirming that longevity is to some extent determined by genetic mechanisms [24,25]. Identification of genetic variation influencing population mortality and specific aspects of successful aging may help characterize the overarching pathways and physiological processes that determine risk for common age-related diseases. Conversely, the study of age-related disease may provide greater insight into the molecular mechanisms that contribute to the aging process. In this exploratory study involving more than 750 controls free of neurological disease, our findings indicate that in addition to its known role in PD, 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. More specifically, 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

Although not of primary interest in this study, it is worth highlighting the significant associations of SNCA SNPs with PD that were observed in this study and previous studies [15–19,21]. Protective effects were observed for rs13752519 and rs1372520,

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Table 2. Single SNP associations with PD.

Minor allele count and frequency Chr4: (bp)* SNP Minor allele PD cases Controls OR (95% CI) P-value 90637010 rs356218 A 335 (39%) 505 (33%) 1.49 (1.15, 1.92) 0.002 90653134 rs17180453 T 83 (10%) 124 (8%) 1.24 (0.89, 1.71) 0.20 90657491 rs3775423 T 84 (10%) 125 (8%) 1.31 (0.95, 1.82) 0.10 90678541 rs2736990 G 459 (54%) 724 (47%) 1.39 (1.04, 1.85) 0.026 90678798 rs2572324 G 303 (36%) 447 (29%) 1.42 (1.10, 1.82) 0.006 90687507 rs3796661 T 29 (3%) 44 (3%) 1.16 (0.69, 1.95) 0.57 90707947 rs2737033 C 295 (35%) 408 (27%) 1.64 (1.28, 2.10) ,0.001 90709741 rs3775439 A 121 (14%) 217 (14%) 0.95 (0.72, 1.25) 0.70 90712629 rs10014396 C 105 (12%) 188 (12%) 0.92 (0.69, 1.23) 0.58 90716177 rs9995651 G 47 (6%) 69 (4%) 1.30 (0.87, 1.96) 0.21 90721637 rs2583959 G 288 (34%) 401 (26%) 1.62 (1.27, 2.08) ,0.001 90745707 rs2737012 A 287 (34%) 399 (26%) 1.62 (1.27, 2.08) ,0.001 90757309 rs1372519 A 155 (18%) 339 (22%) 0.76 (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) ,0.001 90757845 rs2619362 T 94 (28%) 66 (23%) 1.61 (1.26, 2.07) ,0.001 90758389 rs2301135 G 436 (53%) 721 (49%) 1.24 (0.92, 1.68) 0.15 90759047 rs2619363 T 286 (34%) 400 (26%) 1.59 (1.24, 2.04) ,0.001 90760828 rs2583988 T 283 (33%) 398 (26%) 1.56 (1.22, 2.01) ,0.001

PD=Parkinson’s disease. SNP=single nucleotide polymorphism. MA=minor allele. OR=odds ratio. CI=confidence interval. *Chromosomal positions based on the February 2009 (GRCH37/hg19) genome assembly [SNCA is located at Chr4;90,645,251–90,759,447]. ORs, 95% CIs, and p-values result from logistic regression adjusted for age and gender. ORs correspond to presence vs. absence of the minor allele. doi:10.1371/journal.pone.0042877.t002