neurological disease is relatively small, and therefore the possibility of 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 evaluation 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.

which were in strong LD, while risk effects were also noted for a number of other SNPs that were also in relatively high LD. 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 that were observed in this study provide additional support for all of these findings and also further underscore the pleiotrophic 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, though requiring validation in an indepen- dent series, suggest that further study of the role of SNCA variation in aging and cognitive function is warranted.

Several limitations are important to take into account in the interpretation of our results. There are other factors that are likely associated with survival free of neurological disease for which we did not collect information, and as such we cannot rule out the possibility that the associations of SNCA with survival free of neurological disease that we identified may be due in part to confounding factors. Also, owing to the exploratory nature of the study, we made no adjustment for multiple testing. The statistically significant decreasing frequencies of the minor allele for rs10014396 and rs3775439 as age increased in controls would not have remained significant after such an adjustment (P#0.0058 considered significant after permutation adjustment for multiple testing), and therefore it is important to highlight that our findings require validation in an independent series of healthy individuals. Related to this, our sample size of more than 700 controls free of

Acknowledgments

We would like to thank all those who have contributed to our research.

Author Contributions

Conceived and designed the experiments: MMC RJU ZKW NRGR OAR. Performed the experiments: AISO OAR. Analyzed the data: MGH NND. Contributed reagents/materials/analysis tools: OAR ZKW NRGR. Wrote the paper: MGH OAR.

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