Genetics and athletic performance: a systematic SWOT analysis of non-systematic reviews

Exercise genetics/genomics is a growing research discipline comprising several Strengths and Opportunities but also deals with Weaknesses and Threats. This “systematic SWOT overview of non-systematic reviews” (sSWOT) aimed to identify the Strengths, Weaknesses, Opportunities, and Threats linked to exercise genetics/genomics. A systematic search was conducted in the Medline and Embase databases for non-systematic reviews to provide a comprehensive overview of the current literature/research area. The extracted data was thematically analyzed, coded, and categorized into SWOT clusters. In the 45 included reviews five Strengths, nine Weaknesses, six Opportunities, and three Threats were identified. The cluster of Strengths included “advances in technology”, “empirical evidence”, “growing research discipline”, the “establishment of consortia”, and the “acceptance/accessibility of genetic testing”. The Weaknesses were linked to a “low research quality”, the “complexity of exercise-related traits”, “low generalizability”, “high costs”, “genotype scores”, “reporting bias”, “invasive methods”, “research progress”, and “causality”. The Opportunities comprised of “precision exercise”, “omics”, “multicenter studies”, as well as “genetic testing” as “commercial”-, “screening”-, and “anti-doping” detection tool. The Threats were related to “ethical issues”, “direct-to-consumer genetic testing companies”, and “gene doping”. This overview of the present state of the art research in sport genetics/genomics indicates a field with great potential, while also drawing attention to the necessity for additional advancement in methodological and ethical guidance to mitigate the recognized Weaknesses and Threats. The recognized Strengths and Opportunities substantiate the capability of genetics/genomics to make significant contributions to the performance and wellbeing of athletes.


Introduction
Current findings approximate the degree of genetic heritability contributing to athletic performance to be around 50%, wherein endurance-related traits demonstrate a range of 44%-68% and strength-related traits present a range of 48%-56%. (Zempo et al., 2017;Miyamoto-Mikami et al., 2018) Accordingly, other factors such as environment, different training methods, diets, etc. account for the remaining variation of performance between athletes. Furthermore, it is important to note that environmental factors have the potential to modulate gene expression, without inducing modifications in the underlying genetic code. This phenomenon, commonly referred to as epigenetics, plays a pivotal role in regulating various physiological processes. (Widmann et al., 2019) The genetic code is a "set of rules" to define how deoxyribonucleic acid (DNA) is translated into amino acids, the building blocks of proteins. DNA consists of four nucleotides: Adenine, Thymine, Cytosine, and Guanine. (Minchin and Lodge, 2019) A genetic variant describes different variants of a particular DNA sequence, and the most common type involves the substitution of a single nucleotide, known as Single-Nucleotide Variants (SNVs). (Robert and Pelletier, 2018) Genetic variants contribute to different observable characteristics of individuals (i.e., phenotypes or traits) such as muscle fiber distribution.
A good example for describing the involvement of genes in exercise is the ACTN3 gene. This gene codes for the alpha-actinin-3 protein, which is responsible for producing forceful muscle contractions. (Houweling et al., 2018) A stop-codon variant (rs1815739; R577X) results in a non-functional protein (i.e., XX genotype) and individuals carrying this genotype lack the ACTN3 protein. In contrast, the R allele (i.e., RX or RR genotype) results in a functional ACTN3 protein. Interestingly, power and strengths athletes more frequently possess the functional protein when compared to endurance athletes. Baltazar-Martins et al., 2020) Therefore, the R allele has been linked to power/strengths sports and the XX genotype to endurance sports.
One aim of identifying exercise-related variants is the implementation of "precision exercise", following precision medicine.  Precision approaches to training and lifestyle interventions consider the inherent individual differences in genes, environmental factors, and lifestyle, in order to eschew generic and uniform "one size fits all" approaches. Instead, personalized and tailored training regimens and lifestyle interventions aim to optimize performance and/or health outcomes, (Ramaswami et al., 2018), reduce the risk of injury, and identify potential areas of talent in each unique individual. (Montalvo et al., 2017;Ross et al., 2019) In 1998, the first gene (ACE gene) for explaining athletic performance was identified. (Montgomery et al., 1998) At that time, scientists sought to discover the sports gene. Instead, hundreds of variants were found, which likely altogether contribute to athletic performance. Hence, athletic performance is considered a complex trait regulated by the presence of many variants, gene-by-gene, and gene-by-environment interactions, as well as epigenetic influences ultimately challenging the investigation of complex traits. (Rowe and Tenesa, 2012;Ehlert et al., 2013) However, the advent of next-generation sequencing techniques and the integration of molecular methodologies have facilitated the emergence of a comprehensive research paradigm, known as "multi-omics." This approach allows for the examination of complex traits through a holistic lens, thereby enabling a more thorough investigation of biological phenomena. (Sellami et al., 2021) Nowadays, it is well known that intricate molecular networks underlie exercise-related traits and genomics may explain a large amount of the variance observed in exerciserelated traits. Tanisawa et al., 2020;Ginevičienė et al., 2022) By 2021, more than 220 variants have been linked to various exercise-related traits (e.g., elite athlete status, endurance, strength, power, speed, recovery, injury, etc.). (Ahmetov and Fedotovskaya, 2015;Ahmetov et al., 2016;Ahmetov et al., 2022;Silva et al., 2022) Moreover, genotype scores and prediction models for personalized training strategies have been developed and implemented. (Guilherme and Lancha, 2020;Pranckeviciene et al., 2021;Yang et al., 2021) In recent times, private direct-to-consumer genetic testing companies sell online sport-related genetic tests.  These companies employ marketing claims, such as the following: "To reach the top in the sporting world, it is not enough to train hard; you have to train intelligently, to know yourself and how genetics influences sport is the best starting point" (www.24genetics.com). These assertions may seem appealing to athletes seeking to improve their performance. However, the field of exercise genetics/genomics is not free of challenges and potential drawbacks. These include issues such as small sample sizes, inconsistent findings, and ethical concerns surrounding gene doping involving the manipulation of genetic material to enhance athletic performance. (Cantelmo et al., 2020) In conclusion, exercise genetics deals with many "Strengths", "Weaknesses", "Opportunities", and "Threats" (SWOTs).
A SWOT analysis identifies current strengths, future opportunities, areas of weakness that require attention, and potential threats. It allows to assess the progress of a certain topic at a certain point in time, identifies research gaps, and offers future directions. (Helms and Nixon, 2010) As such, a SWOT analysis is an efficient and powerful tool to generate meaningful information for strategic decision-making and to guide the development of future effective action plans. (de-Madaria et al., 2022) In addition, numerous systematic (e.g., systematic reviews/meta-analysis) and non-systematic (e.g., opinion papers, commentaries, narrative reviews, scoping reviews) publications have summarized the evidence of exercise genetics/genomics. Non-systematic reviews are considered an important tool for examining different theoretical conceptualizations, constructs, and/or relationships. (Baumeister and Prinstein, 2013) The fusion of existing reviews allows a synthesis of current evidence thereby stimulating a broader comprehension of research questions. (Gates et al., 2020) To our knowledge, within the exercise genetic/genomic literature, no "overview of non-systematic reviews" about "Strengths", "Weaknesses", "Opportunities", and "Threats" exists. We therefore aimed to comprise an overview of non-systematic reviews to highlight the current Strengths, Weaknesses, Opportunities, and Threats of exercise genetics/genomics.

Study design, reporting guidelines, research protocol
In this "systematic SWOT overview of non-systematic reviews" (sSWOT), we summarized the i) Strengths, ii) Weaknesses, iii) Opportunities, and iv) Threats of this topic. The "Reporting guideline for overviews of reviews of healthcare interventions: development of the PRIOR statement guidelines" has recently been published (2022). (Gates et al., 2022) Since this guideline was established for overviews of systematic reviews focusing on healthcare interventions these standards are not applicable for our purpose. Hence, we followed the "reporting checklist for overviews of reviews" developed by Onishi andFurukawa in 2016 (Onishi andFurukawa, 2016) (see electronic Supplementary Material (ESM) 1 for the checklist). Sometimes, overview of reviews are also referred to as "meta-reviews", "reviews of reviews," or "umbrella reviews". (Tsagris and Fragkos, 2016) The research protocol is based on the "preferred reporting items for systematic review and metaanalysis protocols" (PRISMA-P) and accessible at the open science framework (DOI 10.17605/OSF.IO/TVKUM).

Search strategy and eligibility criteria
We performed a systematic literature search, in accordance with the PRISMA-S guidelines (Rethlefsen et al., 2021) on 19 th of May 2022 by searching the Medline and Embase databases. The search was updated on 8 th of January 2023. We employed the following search terms: athlete, athletic, exercise, genetics, and genomics. We applied the "review" filter to increase the precision of the search results Salvador-Oliván et al., 2021) and limited the search to "title" and "abstracts" only with no date restriction. ESM 2 displays the full search strategy. Nonsystematic reviews (e.g., narrative and scoping reviews, commentaries, or opinion papers) in English with the topic of exercise genetics/genomics were eligible for inclusion. We excluded reviews aiming at specific sport disciplines and/or genetic variants or genes (e.g., injury, nutrition, speed, ACE, ACTN3, etc.). Furthermore, systematic reviews, primary studies, animal studies, conference abstracts, and case studies were also excluded. The retrieved reviews were extracted to Endnote (Clarivate Analytics, Philadelphia, Pennsylvania, United States) and automatically screened for duplicates. The title and abstract were screened by one reviewer (MK). In case that a review seemed appropriate for inclusion, the full text was read and when the full text was not available, we contacted the authors. Finally, all included reviews were screened for crossreferences to minimize the chance of missing relevant reviews.

Data extraction and data items
The main investigator (MK) extracted the data using Excel, with an 8-week wash out period. The two data extraction sheets were compared and in case of detection of major differences in extracted themes, the reviews of interest were read once more. We extracted the following items: first author's name, publication year, title, Strengths, Weaknesses, Opportunities, and Threats. Risk of bias and certainty assessment of the non-systematic reviews was not applicable.

Data synthesis
The extracted data was thematically analyzed and structured into SWOTs. (Braun and Clarke, 2006) The coding strategy consisted of three stages: i) initial coding -remaining open to all possible themes indicated by initial readings of the reviews, (Charmaz, 2006;Corbin and Strauss, 2008), ii) focused coding-categorizing the data inductively based on thematic similarity, (Charmaz, 2006), and finally iii) theoretical codingintegrating thematic categories. (Saldaña, 2021) In the first cycle, open descriptive codes derived directly from the articles (e.g., integration of novel algorithm approaches, results from candidate gene study designs, statistical shortcomings such as multiple testing). Full sentences were treated as unique items on the data extraction sheet and coded to generate a range of information. In a second step, a focused thematic analysis identified patterns among the literature to confirm links between the openly coded data. Thematic phrases (e.g., advances in technology, study design, methodology) were consequently developed and reapplied to coded items in the data extraction sheet. In the third step, the thematic phrases were ordered according to frequency and aggregated into one of the four categories reflecting the scope of this overview: i) Strengths, ii) Weaknesses, iii) Opportunities, and iv) Threats.

Theme: gene doping
The last theme identified by the thematic analysis and highlighted by several reviewers was linked to "gene doping/ editing". (Sharp, 2008;Ostrander et al., 2009;Lippi et al., 2010;Vlahovich et al., 2017;Tanisawa et al., 2020;Varillas-Delgado et al., 2022) Gene doping/editing involves manipulating genetic material and regulating gene expression (e.g., increasing or decreasing the production of certain enzymes or proteins) to enhance athletic performance. (Cantelmo et al., 2020) One author stressed the possible side effects of gene editing. (Varillas-Delgado et al., 2022) Furthermore, the AIS-Athlome consortium-FIMS joint statement (2017) stated: "There is no role for gene-editing for the purposes of performance enhancement and all genetic manipulations are banned under the World Anti-Doping Agency".  According to Varillas Delgado et al. (2022) it is "unclear if there will ever be capacity to detect any type of gene modification by traditional laboratory techniques". (Varillas-Delgado et al., 2022) In addition, "DNA testing and gene editing with embryos" was outlined as potential Threat. ) "Designing athletes with extraordinary athletic performance by using gene-editing technique would be a real threat in terms of keeping sport fair, clean and protecting athlete health" according to the sport and exercise genomics consensus update 2019.  4 Discussion

Strengths and limitations
i) This is the first "overview of non-systematic reviews" related to exercise genetics/genomics including 45 reviews. By using a sSWOT approach, we used a systematic and efficient way to summarize the Strengths, Weaknesses, Opportunities, and Threats on the topic. ii) By searching two databases and reading the cross-references, we minimized the chance of missing relevant reviews. iii) Further, we employed a thematic analysis with three coding steps thereby increasing the internal validity of this overview. (Braun and Clarke, 2006;Nowell et al., 2017) iv) We strictly followed the study protocol and applied a checklist for conducting overviews of reviews. (Onishi and Furukawa, 2016) v) Finally, we used a systematic and transparent approach throughout the overview process in line with the European recommendations for research integrity. (Foundation and Academies, 2011) This overview is not without limitations. i) As we included nonsystematic reviews only, a quality assessment of the included reviews was not performed. Non-systematic reviews are prone to selection bias and may represent subjective opinions (e.g., positive or negative attitudes). (Yuan and Hunt, 2009) ii) We cannot rule out that themes have been missed in the current analysis. iii) One reviewer conducted the literature search and performed the data extraction. However, data extraction was performed twice within an 8-week wash out period thereby increasing the internal validity of the current report. iv) Finally, we excluded discipline-(e.g., endurance, strengths/power, team sports, injury, nutrition, psychological traits, etc.) and polymorphism-specific reviews. Interested readers are referred to the contemporary systematic review conducted by Ahmetov et al. (2022) which provides a comprehensive summary of the currently established genetic variants (n = 220) associated with athletic performance in a general context.  Readers are further referred to following discipline specific reviews: endurance athletes, (Konopka et al., 2022), power/strengths athletes, (Maciejewska-Skrendo et al., 2019), combat sports, (Youn et al., 2021), cardiorespiratory fitness (i.e., the largest genome-wide association study to date with a non-athletic population), (Bye et al., 2020), injury, (Appel et al., 2021;Lim et al., 2021), nutrition, (Guest et al., 2019;Nieman, 2021), and psychology related reviews. (Silva et al., 2022) We also excluded reviews Frontiers in Genetics frontiersin.org 10 related to topics such as "doping", "epigenetics", and "omics" as we were interested in SWOTs linked to exercise genetics/genomics in general and not related to specific topics. The excluded reviews likely would influence the results of the applied analysis by increasing the number of identified themes such as "empirical evidence", "omics and technology", or "doping".

Conclusion
We conducted a "systematic SWOT analysis of nonsystematic reviews" including 45 reviews with the aim to identify the current SWOTs linked to exercise genetics/ genomics. The thematic analysis identified five themes for Strengths and nine themes for Weaknesses. Six themes were linked to Opportunities, and three were clustered into Threats. Despite the complexity of exercise genetics/genomics, the present overview demonstrates that exercise genetics/genomics has future potential to assist athletes and coaches to enhance or maintain performance and health. The notion of precision exercise, whereby global large-scale consortia endeavor to establish correlations between genomics, multi-omics, and exercise-related traits, appears to hold considerable promise. This overview also highlights the need for further development in methodological and ethical guidance to minimize the identified Weaknesses and Threats. Furthermore, it seems justifiable to raise concerns regarding the relatively limited predictive capacity of genetic profiles. Nonetheless, the purpose of polygenic risk scores is not to make precise predictions about athletic performance, success, or health. Rather, genetic profiles should be utilized as an additional tool to enhance complex training methods. Noteworthy, the possession of an advantageous genotype does not guarantee the manifestation of athletic phenotypes, since a myriad of psychological, social, and environmental factors exert a substantial influence on athletic performance, and genetics only accounts for a fraction of the inter-individual variability observed. Nevertheless, the achievement of world-class levels will likely prove arduous without a favorable genetic profile.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author contributions
MK and MZ contributed to conceptualization and design of the study. MK performed literature search and wrote the initial draft of the manuscript. MK screened all articles, selected included articles, and critically appraised all included articles. MK summarized data from the included articles. BS, GR, and MZ critically read and commented the manuscript, and approved the submitted version. All authors contributed to the article and approved the submitted version.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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