Is There Utility to Genetic Information in Elite Sport? by Craig Pickering

Is there utility to genetic information in elite sport? by Craig Pickering A thesis submitted in partial fulfilment for the requirements for the degree of Professional Doctorate in Elite Performance at the University of Central Lancashire February 2020 STUDENT DECLARATION FORM Type of Award Professional Doctorate in Elite Performance School School of Sport & Wellbeing Sections marked * delete as appropriate 1. Concurrent registration for two or more academic awards I declare that while registered as a candidate for the research degree, I have not been a registered candidate or enrolled student for another award of the University or other academic or professional institution 2. Material submitted for another award I declare that no material contained in the thesis has been used in any other submission for an academic award and is solely my own work 3. Collaboration Where a candidate’s research programme is part of a collaborative project, the thesis must indicate in addition clearly the candidate’s individual contribution and the extent of the collaboration. Please state below: _N/A________________________________________________________________ 4. Use of a Proof-reader No proof-reading service was used in the compilation of this thesis. Signature of Candidate Print name: Craig Pickering ABSTRACT Variation between individuals in response to a stimulus is a well-established phenomenon. This thesis discusses the drivers of this inter-individual response, identifying three major determinants; genetic, environmental, and epigenetic variation between individuals. Focusing on genetic variation, the thesis explores how this information may be useful in elite sport, aiming to answer the question “Is there utility to genetic information in elite sport?” The current literature was critically analysed, with a finding that the majority of exercise genomics research explains what has happened previously, as opposed to assisting practitioners in modifying athlete preparation and enhancing performance. An exploration of the potential ways in which genetic information may be useful in elite sport then follows, including that of inter- individual variation in response to caffeine supplementation, the use of genetic information to assist in reducing hamstring injuries, and whether genetic information may help identify future elite athletes. These themes are then explored via empirical work. In the first study, an internet-based questionnaire assessed the frequency of genetic testing in elite athletes, finding that around 10% had undertaken such a test. The second study determined that a panel of five genetic variants could predict the magnitude of improvements in Yo-Yo test improvements following a standardised training programme in youth soccer players. The third study demonstrated the effectiveness of a panel of seven genetic variants in predicting the magnitude of neuromuscular fatigue in youth soccer players. The fourth and final study recruited five current or former elite athletes, including an Olympic Champion, and created the most comprehensive Total Genotype Score in the published literature to date, to determine whether their scores deviated significantly from a control population of over 500 non-athletes. The genetic panels were unable to adequately discriminate the elite performers from non-athletes, suggesting that, at this time, genetic testing holds no utility in the identification of future elite performers. The wider utilisation of genetic information as a public health tool is discussed, and a framework for the implementation of genetic information in sport is also proposed. In summary, this thesis suggests that there is great potential for the use of genetic information to assist practitioners in the athlete management process in elite sport, and demonstrates the efficacy of some commercially available panels, whilst cautioning against the use of such information as a talent identification tool. The major limitation of the current thesis is the low sample sizes of many of the experimental chapters, a common issue in exercise genetics research. Future work should aim to further explore the implementation of genetic information in elite sporting environments. 3 TABLE OF CONTENTS Chapter 1 – Introduction 13 1. Why genetic testing? 13 2. Is there utility to genetic testing in elite sport? The structure of the thesis 15 Section 2 – Literature Review 17 Chapter 2 – Inter-subject variation in exercise adaptation: Contributing factors & the potential utility of genetic testing 18 1. Introduction 18 2. Inter-subject variation in response to training 18 2.1 Inter-individual variation following aerobic training 19 2.2 Inter-individual variation following resistance training 19 2.3 Other reported inter-individual variations 20 2.4 Exercise response: Modality specific? 20 3. Potential mechanisms driving the individual response 21 3.1 Genetics 21 3.1.1 Gene polymorphisms and exercise adaptation 23 3.2 Environmental factors 25 3.2.1 Individual history 25 3.2.2 Programme design 26 3.2.3 Psycho-emotional factors 26 3.2.3.1 Factors affecting psycho-emotional response 27 3.2.4 Nutrition 28 3.3. Summarising gene-environment interactions 29 3.4 Epigenetics 30 3.4.1 DNA methylation 31 3.4.2 Histone modifications 32 3.4.3 Non-coding RNA 32 3.4.4 Genetic influences on epigenetic modifications 33 3.4.5 Environmental influences on epigenetic modifications 33 4. A final model to explain the causes of inter-subject variation 34 5. Harnessing this knowledge to improve performance 35 6. Conclusion & future directions 37 Chapter 3 – Contemporary issues regarding exercise non-response and exercise genomics 39 Part 1 – Do non-responders to exercise exist? 39 1. The terminology problem: “Non-responder” vs “Did not respond” 39 2. Exercise non-response: Statistical insights 40 3. Should exercise non-response be a concern? 41 4. “Did not respond” – potential interventions 42 4 5. Summary – Do non-responders to exercise exist? 43 Part 2 – Exercise genetics: Seeking clarity from noise 44 1. Introduction 44 2. Association or causation? 44 3. Are these relationships consistent? 45 4. Effective utilisation 46 5. Summary 46 Chapter 4 – Methodology 47 1. A brief history of sports genetics research – from twins, to candidate gene association studies, to GWAS 47 2. Just how much utility does current sports genetics research bring? 48 3. Bridging the gap? 49 4. The DNAFit test 50 5. Why use Total Genotype Scores? 51 6. Methodology for thesis 52 7. Summary 55 Section 3 – Joining the dots: a theoretical approach to the utilisation of genetic information in sport 56 Chapter 5 – Are the current guidelines on caffeine use in sport optimal for everyone? Inter-individual variation in caffeine ergogenicity, and a move towards personalised sports nutrition 57 1. Introduction 57 2. Inter-subject variation in the response to caffeine 59 3. Why does this individual response exist? 59 3.1 The genetics of individual variation in caffeine response 59 3.1.1 CYP1A2 60 3.1.2 ADORA2A 61 3.1.3 Potential mechanisms – a role for caffeine timing? 64 3.1.4 Indirect impact of genetic variation on exercise performance 64 3.2 Environmental factors affecting caffeine response 65 3.3 Epigenetic modifiers of caffeine response 66 3.4 “Non-responder” vs “Did not respond” 66 4. Conclusion – what next? 67 Chapter 6 – ACTN3: More than just a gene for speed 70 1. Introduction 70 2. ACTN3 as a modulator of training response 71 3. ACTN3 as a modulator of post-exercise recovery 73 4. ACTN3 as a modulator of exercise-associated injury risk 76 5. Discussion 78 5 6. Conclusion 79 Chapter 7 – Genes, hamstring injury, and the response to eccentric training 81 1. Introduction 81 2. SNPs potentially involved in HSI 83 3. A genetic influence on the response to mechanical loading 84 3.1 Genetic insights into the response to eccentric training 85 3.1.1 Genetics and strength gains 85 3.1.2 Genetics and muscle fascicle length 85 3.1.3 Genetics and post-exercise recovery 86 4. Conclusion – using this information 87 Chapter 8 – Can genetic testing identify “talent” (whatever that might be)? 89 Part 1 – Could genetic information ever be used for talent identification? 89 1. Introduction 89 2. Why can’t genetic information currently be used for talent ID? 90 3. What further knowledge is required to potentially use genetic information for talent identification? 92 3.1 Genome-Wide Association Studies 92 3.2 Rare variants 93 3.3 Signal or noise? 93 3.4 A predictive threshold? 94 3.5 Epigenetic modifications 94 3.6 Lessons from disease prediction 94 4. Is genetic testing for talent ethical? 96 5. What could genetic testing potentially be used for? 96 6. Conclusion 97 Part 2 – Can the ability to adapt to exercise be considered a talent – and if so, can it be tested for? 98 1. Introduction 98 2. The hereditary aspect of talent 99 3. Is the ability to adapt to exercise a talent? 100 3.1 Is exercise adaptation partially innate? 102 3.2 Are the full effects of this talent not fully evident at an early age? 102 3.3 Are there early indications of this talent? 102 3.4 Do only a minority of people possess this talent? 103 3.5 Is this talent domain specific? 103 3.6 Can exercise adaptation be considered a talent? 103 4. Can this talent be tested for? 104 5. Conclusion 105 Section 4 – Practical use of genetic information in sport 106 6 Chapter 9 – The frequency of, and attitudes towards, genetic testing amongst athletes and support staff 107 1. Introduction 107 2. Methods 108 3. Results 109 3.1 Participant demographics 109 3.2 Beliefs around the impact of genetics in sporting phenotypes 110 3.3 Prevalence of genetic testing within sport 110 3.4 Attitudes towards genetic testing 111 3.5 Experiences of genetic testing 112 4. Discussion 113 4.1 Implications for future work 115 4.2 Limitations 115 5.

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