Is It Time to Change the Ground Rules of Exercise-Related Genomics Research?

As research seeks to decipher the effect of physical activity on skeletal muscle health, there is pressure to better understand the contribution of genetic influences in the context of exercise stimuli. During the past decade, the tools to understand how genetic underpinnings such as single nucleotide polymorphisms (SNPs) influence exercise performance phenotypes have evolved at a rapid rate, resulting in a substantial number of publications. To keep readers informed of publications associating SNPs with overall health and performance, Bouchard et al. have provided annual cumulative reviews of the exercise genomics literature since 2000 (2,6,7). The pace of genomics research, however, has forced Bouchard et al. to take a more selective approach in the papers included in the 2010 year-end review published in this issue of Medicine & Science in Sports & Exercise® (4). Only the papers deemed to have met an acceptable standard as defined by sample size, quality of measurements, study design, and quality of genotyping are included (4). The end result is that only a scant percentage (<20%) of publications met this criteria. Hagberg et al. (4) conclude that, although progress is being made, more high-quality research designs and replication studies with larger sample sizes are urgently needed. The consequence of the underpowered approach regarding sample size is that many genetic association studies, for example, the effect of the ACTN3 gene on muscle function, have yielded inconclusive results or reported false positives and negatives (4). This scenario begs the question of whether the field is taking a stringent-enough approach to the quality of science if only 20% of the publications each year are considered to have met an acceptable standard. To this end, it seems appropriate to propose that a set of "ground rules" are used as stringent criteria against which future projects are gauged-from inception to publication. These ground rules would incorporate evidence-based guidelines and regulations established from a Cochrane-type systematic review of the current literature. The Cochrane approach is currently used to compile American College of Sports Medicine Position Stands. Based on the most recent evaluation of the exercise genomics literature by Hagberg et al. (4) and a timely article by Durbin et al. (3), it is reasonable to suggest that ground rules include large sample sizes (>1000 subjects), subject cohorts with population and geographical diversity, and more stringent P values (e.g., <1.0 × 10−3). For this field to advance and provide scientists and clinicians with relevant and reliable information, it is critical that funding agencies, editors, and reviewers become responsible for reviewing grants and publications with specific consideration of these criteria. Collectively, these ground rules would help align important research questions with scientifically thorough and reliable research studies thereby preventing wasted time, dollars, and scientific efforts. This approach would also foster collaboration among laboratories and result in more fruitful research efforts in the exercise genomics field. At first glance, studies that enforce population diversity seem improbable and difficult to execute. However, when the exercise genomics field was still in its infancy, two studies were initiated that followed this model of large sample sizes, rigorous exercise interventions, and population diversity. The multisite Functional Single Nucleotide Polymorphisms Associated with Muscle Size and Strength (FAMUSS) study included 874 subjects representing ethnic groups from seven sites within the United States and one site in Europe (8). The Health, Risk factors, exercise Training and Genetics (HERITAGE) family study used a similar approach with 834 subjects recruited from five sites in the United States and Canada (1). This approach is necessary to overcome geographical phenotypes associated with specific regions. In fact, 10 years later, a similar, yet more robust, model is being used for the 1000 Genomes Project (3). The goal of the 1000 Genomes Project is to characterize 95% of variants in genomic regions using high-throughput sequencing technologies that have an allele frequency of at least 1% (classical definition of a SNP). As suggested in the "ground rules," this project will include nearly 1000 subjects from each of the five major population groups-Europe, East Asia, South Asia, West Africa, and the Americas. It might be argued that if these ground rules become accepted, only large, well-funded scientific teams will be able to participate in this type of scientific research. Indeed, one of the most cutting-edge and thorough SNP association studies has been genome-wide association studies (5), which are higher-throughput approaches that require thousands of subjects at a cost of approximately $1000 per subject. In the case of genome-wide association studies, a suitable model for multisite collaborations is to include well-funded national organizations with access to novel technology along with smaller organizations (i.e., academic and government organizations) with access to subjects and the ability to conduct performance and health-related testing. There is substantial enthusiasm about the future relevance of genomics in exercise and health-related fields. However, without changing the current approach, we are at risk of continuing to provide inconclusive or inaccurate data that will certainly slow the evolution and clinical application of this field. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Maria L. Urso, PhD US Army Research Institute of Environmental Medicine Natick, MA

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