Evaluation of the Role of SNCA Variants in Survival without Neurological Disease 

G. Heckman1*, Alexandra I. Soto-Ortolaza2, Nancy N. Diehl1, Minerva M. Carrasquillo2, J. Uitti3, Zbigniew K. Wszolek3, Neill R. Graff-Radford3, Owen A. Ross2 

1 Biostatistics Unit, Mayo Clinic, Jacksonville, Florida, United States of America 
2 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America 
3 Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America 

Abstract 

Background: A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability or preservation of high physical and cognitive function. Many behavioral, biomedical and psychological factors have been linked with these various measures of successful aging; however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder and variants in the alpha-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease.

Methods: We utilized 769 controls without neurological disease (Mean age: 79 years; Range: 33-99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk.

Results: There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD.

Conclusions: In addition to its documented roles in PD and alpha-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.

* E-mail: heckman.michael@mayo.edu 

Introduction 

Aging can be defined as a progressive, generalized impairment of function resulting in a loss of adaptive response to stress and an increasing risk of age-associated disease [1,2]. Within this definition lies the paradoxical idea that individuals can age in a healthy manner, so-called successful aging, which is a topic that has received increased attention as a result of the dramatic increase in human life expectancy witnessed during the past century. While longevity is clearly a key part of aging in a healthy manner, it is equally clear that it is not the only component and that other factors require consideration [3]. The concept of successful aging was introduced by Rowe and Kahn, distinguishing usual aging from successful aging and referring to successful aging as freedom from disease and disability, preservation of high physical and cognitive function, and engagement in social and productive activities [4,5]. Many different attempts have been made to identify characteristics associated with the various measures of successful aging that have been proposed. The majority of these reports have investigated demographic, behavioral, biomedical or psychological factors and have identified predictors such as absence of arthritis, better activities of daily living and not smoking among many others [6,7]. However, fewer studies have examined genetic predictors. The identification of genetic factors related to specific aspects of successful aging has several potential benefits, for instance, shedding light on the underlying biological systems and processes involved in aging successfully and possibly allowing for the identification of people who possess harmful variants of those genes, for whom intervention could potentially increase the likelihood of successful aging.

Due to their links to specific aspects of successful aging such as disease, physical functioning and cognitive functioning, the study of age-related disorders offers promise in further understanding the mechanisms involved in the aging process. Parkinson's disease (PD) is one of the most prevalent age-related neurodegenerative disorders, with approximately 1.5% of the population older than sixty-five years being affected [8,9], and at the center of genetic PD research is the alpha-synuclein gene (SNCA). Point mutations in SNCA were the first mutations identified in familial PD [10]. Subsequent studies showed alpha-synuclein to be the major protein component of the pathologic inclusion observed in PD, the Lewy body [11,12]. Identification of genomic multiplication of the SNCA gene in familial PD demonstrated that over-expressionParticipants in the study included controls and Parkinson's disease (PD) cases, seen at Mayo Clinic Florida. Unrelated controls were deemed free of neurological disease by a neurologist and had no family history of neurological disease. The mean age of the controls was 79±6.11 SD years (range: 33-99 years), and 385 (50%) were male. All controls were of European ancestry and white. Controls were mostly unrelated spouses/caregivers of neurological patients, and a subset of these controls was included in an aging sibpair study [20]. Using this group of controls, the association of SNCA SNPs with age was evaluated since the probability of living longer without neurological disease increases as age without neurological disease increases, and age in these controls is a measure of survival without neurological disease.