Millions of sports-related concussions (SRC) occur each year (1,2). Vulnerability to these injuries is variable. Additionally, athletes respond differently to SRC not only in the number of signs and symptoms they exhibit but also in the severity of such symptoms and recovery time. A variety of intrinsic and extrinsic factors have been proposed as influencing the likelihood of suffering an SRC as well as the subsequent postinjury clinical course (3). This article reviews one of these suspected intrinsic factors — the genetic characteristics of the athlete. Findings from the investigation of genetic factors in traumatic brain injury (TBI) (4) have stimulated interest in the role of genetics in predicting risk of injury as well as recovery from SRC (5).
Variation in concussion risk, as well as in concussion severity and outcome, has been hypothesized to be due in part to genetic factors and their interaction with other genetic polymorphisms and environmental factors. Genetic polymorphisms may arise from deletions or insertions of DNA within a particular gene or at a single nucleotide. These can affect normal gene expression and function (6,7). Variation in the human genome results in multiple proteins mediating the cellular response to an impact to the head and/or body of an athlete with the potential to cause an SRC (8).
The level and function of such proteins may be determinants of the physiological consequences, such as oxidative stress, impaired axonal transport, and altered neurotransmission, linked to the initial ionic fluxes, indiscriminate glutamate release, and metabolic uncoupling (9). The genes contributing to synaptic connectivity (GRIN2A), plasticity, and repair (apolipoprotein E [APOE]), calcium influx (CACNA1E), uptake, and deposit of glutamate (SLC17A7) are some examples of some potential biomarkers of concussion susceptibility and recovery (10).
Commercial genetic tests for SRC-related issues have already been marketed, but so far, there seems to be limited demand for such testing (11).
Are Individuals With Certain Genotypes at Greater Risk for SRC?
TBI studies have focused on specific genetic polymorphisms, primarily those within the general APOE gene that has previously been implicated as a risk factor for late-onset Alzheimer’s disease. These studies present mixed results regarding the APOE genotype and associated risk of TBI with some showing increased risk and others no increased risk (5,6).
In contrast, SRC studies have shown no association between the general APOE genotype and increased risk (6,12). Additionally, in a study of military subjects with characteristics similar to college athletes, there was no association noted between the dopamine receptor D2 (DRD2; rs1800497) and increased risk of SRC (13), nor with rs74174284 polymorphism in college athletes (14,15).
The APOE G-219T TT promoter genotype was significantly associated with self-reported concussion risk in a cross-sectional study of college athletes and was significantly associated with sports concussion in a separate study (12,14,16).
A study of 128 South African rugby players found that the APOErs405509 TT genotype may be associated with reduced concussion susceptibility and that the APOE-e4 allele was not associated with reduced concussion susceptibility (17).
The largest prospective cohort study to date published in 2018 included 1056 college athletes and found that a significant association was noted between IL-6R CC genotype and increased concussion risk and between APOE4 allele and reduced concussion risk. IL-6R CC was associated with a three times greater concussion risk and APOE4 with a 40% lower risk (6).
Are Individuals with Certain Genotypes at Greater Risk for Delayed Recovery and/or Long-term Sequelae from SRC?
McCrea et al. (5) suggest “four broad contexts in which genetic variation could modulate outcome:
- 1) modulation of the impact of a given neurotrauma “dose” in terms of injury extent;
- 2) modulation of repair mechanisms, thus impacting trajectory of recovery and ultimate functional outcome;
- 3) modulation of preinjury traits (e.g., resilience) or cognition (cognitive reserve) and;
- 4) interactions between genetic vulnerabilities to neurobehavioral disorders and neurotrauma (i.e., role of comorbidities).”
Two studies investigated gene expression after concussion in a group of 15 collegiate athletes. Comparison of preseason baseline and postinjury samples in these athletes showed differential expression of genes driving immune and inflammatory pathways in the acute phase (6 h post-SRC), and hypothalamic-adrenal-pituitary axis function subacutely (7 d post-SRC) (18,19).
Other investigators prospectively studied the role of variable number tandem repeat alleles in the promoter region of GRIN2A (a gene coding an NMDA glutamate receptor subunit) in 87 collegiate concussed athletes. The long variant of the allele was associated with recovery times over 60 d (20).
Two other studies found an association of the APOEe4 allele with total symptom score, cognitive and physical symptoms, and the presence and severity of headache in a cohort of 42 concussed collegiate athletes assessed a mean of 10 d after injury (21,22).
Another study in a cohort of 40 concussed collegiate athletes examined the rs74174284 polymorphism in the promoter region of the SLC17A7 gene and found that the C allele was associated with prolonged recovery times and poorer motor performance (15).
A prospective cohort study of 52 children with mild TBI, concentrations of 5 salivary microRNAs identified prolonged concussion symptoms with 85% accuracy and outperformed standard survey measures of symptom burden. Salivary microRNA levels may represent an accurate, objective, and easily collected measure of prolonged concussion symptom risk (23).
In summary, these studies suggest that genetic assessment has potential for identification of those athletes at greater risk for poor outcomes after suffering SRC, but all of the studies involved small numbers of participants and had high to moderate risk for bias. Large-scale multisite studies are necessary to validate the findings from these pilot studies.
What Are Some Concerns for Genetic Testing for SRC?
Apart from medical implications, there also are legal, ethical, public health, and social concerns when considering any type (not necessarily sports-related) of genetic testing. Examples include access to testing, the use of tests in subgroups that are potentially vulnerable to being abused, risks for psychological stress, and risks for discrimination by insurance companies, employers, and society as a result of testing (24).
Specific to sports participation, athletes could face discrimination on the basis of their genotype. Costs and liability associated with SRC are a rising concern for schools and sports leagues. The ability to predict who is more likely to experience a worse outcome may be of interest to institutions seeking to manage their exposure to risk. Potentially, athletes could be denied participation, or the chance to compete equally for playing time, scholarship money, or professional contracts (25–27). Fortunately, federal legislation helps to mitigate some of these concerns, including “The Genetic Information Nondiscrimination Act of 2008” (28). This law makes it illegal for health insurance providers to use or require genetic information to make decisions about a person’s insurance eligibility or coverage as well as making it illegal for employers to use a person’s genetic information when making decisions about hiring, promotion, and several other terms of employment.
Do Athletes Have an Interest in Genetic Testing as It Relates to SRC?
One recent study evaluated college athletes’ interest in genetic testing on the risk of poor recovery from SRC. Nearly three quarters of athletes expressed some level of interest in genetic testing for increased risk of poor recovery from concussion. Athletes who had experienced a difficult recovery were more likely to report being very interested in genetic testing. This was the first study to acknowledge that athletes are interested in their genetic risk. Athletes in this study demonstrated a lack of understanding about genetic testing protocols including counseling and ethical/legal concerns. Additionally, athletes did not believe genetic testing could affect their involvement in sport (29).
In general, the track record of genetic association studies has been less than optimal. Inconsistency and nonreplication are common features. Most reported associations were ultimately shown to be false, and the results of many genetic studies will not be reproducible (30,31). The overwhelming majority of studies involving genetic factors and SRC have small numbers of study subjects, significant bias risk, and have not been adequately replicated with more rigorous investigations.
There is an obvious need for large-scale, well-designed prospective investigative efforts to validate the role for genetic testing in the management of SRC. A genomewide association study (an observational study of the genomewide set of genetic variants in different individuals to see if any variant is associated with a trait) may be the optimal study design (10). Additionally, it will be important to demonstrate that using genetic testing provides additional benefit to athletes when compared to current approaches.
SRC has a complex pathophysiology, and it is unlikely that a singular diagnostic and prognostic biomarker solution will prevail. Rather, an integrated combination of specific imaging, fluid, and genetic biomarkers is predicted to have the greatest utility to clinical care.
Genetic testing may eventually have utility in determining the factors that influence risk of injury and recovery after SRC but, at this point in time, cannot yet be endorsed as a clinical tool in SRC management.
The author declares no conflict of interest and does not have any financial disclosures.
1. Bryan MA, Rowhani-Rahbar A, Comstock RD, et al. Sports- and recreation-related concussions in US youth. Pediatrics
. 2016; 138:e20154635.
2. Finnoff JT, Jelsing EJ, Smith J. Biomarkers, genetics, and risk factors for concussion. PM R
. 2011; 3:S452–9.
3. McCrory P, Meeuwisse W, Dvorak J, et al. Consensus statement on concussion in sport-the 5th
International Conference on Concussion in Sport held in Berlin, October 2016. Br. J. Sports Med
. 2017; 51:838–47.
4. McAllister TW. Genetic factors in traumatic brain injury. Handb. Clin. Neurol
. 2015; 128:723–39.
5. McCrea M, Meier T, Huber D, et al. Role of advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion: a systematic review. Br. J. Sports Med
. 2017; 51:919–29.
6. Terrell TR, Abramson R, Barth JT, et al. Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study. Br. J. Sports Med
. 2018; 52:192–8.
7. Karki R, Pandya D, Elston RC, Ferlini C. Defining “mutation” and “polymorphism” in the era of personal genomics. BMC Med. Genomics
. 2015; 8:37.
8. Davidson J, Cusimano MD, Bendena WG. Post-traumatic brain injury: genetic susceptibility to outcome. Neuroscientist
. 2015; 21:424–41.
9. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery
. 2014; 75:S24–33.
10. McDevitt J, Krynetskiy E. Genetic findings in sport-related concussions: potential for individualized medicine. Concussion
. 2017; 2. [cited 2018 Nov 7]. Available from: https://www.futuremedicine.com/doi/full/10.2217/cnc-2016-0020
11. Robbins R. Athletes are keeping their distance from a genetic test for concussion risks. August 15, 2016. [cited 2018 Nov 7]. Available from: https://www.statnews.com/2016/08/15/concussion-brain-athletes-genetic-test/
12. Panenka WJ, Gardner AJ, Dretsch MN, et al. Systematic review of genetic risk factors for sustaining a mild traumatic brain injury. J. Neurotrauma
. 2017; 34:2093–9.
13. Tierney RT, Mansell JL, Higgins M, et al. Apolipoprotein E genotype and concussion in college athletes. Clin. J. Sport Med
. 2010; 20:464–8.
14. Terrell TR, Bostick RM, Abramson R, et al. APOE, APOE promoter, and tau genotypes and risk for concussion in college athletes. Clin. J. Sport Med
. 2008; 18:10–7.
15. Madura SA, McDevitt JK, Tierney RT, et al. Genetic variation in SLC17A7
promoter associated with response to sport-related concussions. Brain Inj
. 2016; 30:908–13.
16. Kristman VL, Tator CH, Kreiger N, et al. Does the apolipoprotein epsilon 4 allele predispose varsity athletes to concussion? A prospective cohort study. Clin. J. Sport Med
. 2008; 18:322–8.
17. Abrahams S, McFie S, Patricios J, et al. An association between polymorphisms within the APOE gene and concussion aetiology in rugby union players. J. Sci. Med. Sport
. 2018; 21:117–22.
18. Gill J, Merchant-Borna K, Lee H, et al. Sports-related concussion results in differential expression of nuclear factor-kappaB pathway genes in peripheral blood during the acute and subacute periods. J. Head Trauma Rehabil
. 2016; 31:269–76.
19. Merchant-Borna K, Lee H, Wang D, et al. Genome-wide changes in peripheral gene expression following sports-related concussion. J. Neurotrauma
. 2016; 33:1576–85.
20. McDevitt J, Tierney RT, Phillips J, et al. Association between GRIN2A promoter polymorphism and recovery from concussion. Brain Inj
. 2015; 29:1674–81.
21. Merritt VC, Arnett PA. Apolipoprotein E (APOE) ɛ4 allele is associated with increased symptom reporting following sports concussion. J. Int. Neuropsychol. Soc
. 2016; 22:89–94.
22. Merritt VC, Ukueberuwa DM, Arnett PA. Relationship between the apolipoprotein E gene and headache following sports-related concussion. J. Clin. Exp. Neuropsychol
. 2016; 38:941–9.
23. Johnson JJ, Loeffert AC, Stokes J, et al. Association of salivary microRNA changes with prolonged concussion symptoms. JAMA Pediatr
. 2018; 172:65–73.
24. Fulda KG, Lykens K. Ethical issues in predictive genetic testing: a public health perspective. J. Med. Ethics
. 2006; 32:143–7.
25. Varley I, Patel S, Williams AG, Hennis PJ. The current use, and opinions of elite athletes and support staff in relation to genetic testing in elite sport within the UK. Biol. Sport
. 2018; 35:13–9.
26. Collier R. Genetic tests for athletic ability: science or snake oil? CMAJ
. 2012; 184:E43–4.
27. Guth LM, Roth SM. Genetic influence on athletic performance. Curr. Opin. Pediatr
. 2013; 25:653–8.
28. U.S. Equal Employment Opportunity Comission. The Genetic Information Nondiscrimination Act of 2008. [cited 2018 Nov 7]. Available from: https://www.eeoc.gov/laws/statutes/gina.cfm
29. Hercher LS, Caudle M, Griffin J, et al. Student-athletes’ views on APOE
genotyping for increased risk of poor recovery after a traumatic brain injury. J. Genet. Couns
. 2016; 25:1267–75.
30. Ioannidis JP. Non-replication and inconsistency in the genome-wide association setting. Hum. Hered
. 2007; 64:203–13.
31. Gordon KE. Apolipoprotein E genotyping and concussion: time to fish or cut bait. Clin. J. Sport Med
. 2010; 20:405–6.
32. Terrell TR, Bostick R, Barth J, et al. Multicenter cohort study on association of genotypes with prospective sports concussion: methods, lessons learned, and recommendations. J. Sports Med. Phys. Fitness
. 2017; 57:77–89.