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The genetics of human performance

Nature Reviews Genetics volume 23, pages 40–54 (2022)Cite this article

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Abstract

Human physiology is likely to have been selected for endurance physical activity. However, modern humans have become largely sedentary, with physical activity becoming a leisure-time pursuit for most. Whereas inactivity is a strong risk factor for disease, regular physical activity reduces the risk of chronic disease and mortality. Although substantial epidemiological evidence supports the beneficial effects of exercise, comparatively little is known about the molecular mechanisms through which these effects operate. Genetic and genomic analyses have identified genetic variation associated with human performance and, together with recent proteomic, metabolomic and multi-omic analyses, are beginning to elucidate the molecular genetic mechanisms underlying the beneficial effects of physical activity on human health.

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Fig. 1: VO2 max is affected by the function of numerous organs.
Fig. 2: The hypoxia-inducible factor signalling pathway affects the haematopoietic and vascular systems.
Fig. 3: Metabolic changes with acute exercise converge on PGC1α in skeletal muscle.
Fig. 4: Summary of molecular changes with acute exercise and long-term endurance training.

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Acknowledgements

The authors thank J. W. Knowles, M. E. Lindholm and C. M. Mattsson for their feedback on drafts of this article. D.S.K. thanks L. Han, N. Liu, M. Roy-O’Reilly and G. Salzman for excellent patient care, allowing for the time needed to write this article. D.S.K. also thanks J. K. Rathkey for stimulating conversations on biomechanical efficiency and exercise metabolism.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Daniel Seung Kim, Matthew T. Wheeler & Euan A. Ashley

  2. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA

    Matthew T. Wheeler & Euan A. Ashley

  3. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA

    Euan A. Ashley

  4. Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA

    Euan A. Ashley

Authors
  1. Daniel Seung Kim
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  2. Matthew T. Wheeler
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Contributions

E.A.A. and D.S.K. wrote the article. All authors researched data for the article, had substantial contribution to the discussion of the content, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Euan A. Ashley.

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Competing interests

M.T.W. reports grants and personal fees from Verily, Myokardia and ArrayBio, and consultancy fees from BioTelemetry, outside the submitted work. E.A.A. reports advisory board fees from Apple and Foresite Labs. E.A.A. has ownership interest in Nuevocor, DeepCell and Personalis, outside the submitted work. E.A.A. declares ownership interest in SVEXA, and is a board member of AstraZeneca. D.S.K. declares no competing interests.

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Nature Reviews Genetics thanks I. Ahmetov, N. Fuku and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Athlome Project Consortium: http://www.athlomeconsortium.org/

ExtraMeta: http://www.extrameta.org

Exercise at the Limit — Inherited Traits of Endurance: https://med.stanford.edu/elite.html

MetaMEx: http://www.metamex.eu

Molecular Transducers of Physical Activity Consortium: https://motrpac-data.org

Glossary

Endurance physical activity

(EPA). Human performance that optimizes sustained activity over an extended period of time, such as running, cycling and cross-country skiing. Maximal oxygen uptake (VO2 max) is commonly used as a proxy for maximal capacity for EPA.

Resistance physical activity

(RPA). Human performance that requires muscles to work against an external force, such as weightlifting; individual muscle groups (such as biceps or triceps) can be measured accurately in isolation using dynamometry.

Healthspan

The length of time that a person is healthy and independent in their activities; by contrast, lifespan simply measures the length of time a person is alive but does not factor in quality of life.

Maximal oxygen uptake

(VO2 max). Represents the maximum capacity for endurance physical activity (EPA). It is the maximal rate of oxygen uptake (O2 in ml kg−1 min−1) measured during incremental increases in EPA activity intensity, commonly on a treadmill or stationary bike.

Haplogroups

Combinations of alleles at different regions of the genome (organellar or nuclear) that share polymorphisms inherited from a common ancestor.

Polygenic score

A measure constructed from additive genotypes of variants across multiple genes associated with a trait that can be used to predict from an individual’s genetic sequence their likelihood of having that trait.

Type II/fast-twitch muscle fibre

This muscle fibre type is optimized for resistance physical activity, and is characterized by high force generation but low endurance capability.

Type I/oxidative muscle fibre

This ‘slow-twitch oxidative’ muscle fibre type is optimized for endurance physical activity; it has greater mitochondrial density, which leads to lower force generation but increased resistance to fatigue.

Expression quantitative trait locus

(eQTL). A genetic variant that is associated with a gene expression phenotype.

Cardiac output

The amount of blood the heart pumps through the circulatory system (measured in litres per minute and estimated by multiplying the heart rate by stroke volume). Cardiac output is one of the primary contributors to VO2 max.

Antagonistic pleiotropy

Occurs when a locus or variant has a beneficial effect on one trait but confers deleterious effects on a separate trait.

Epigenetic modifications

Chemical alterations to DNA (most commonly by methylation) or DNA-associated histones (via acetylation, phosphorylation or methylation) that result in heritable changes to gene expression without changing the DNA sequence.

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Kim, D.S., Wheeler, M.T. & Ashley, E.A. The genetics of human performance. Nat Rev Genet 23, 40–54 (2022). https://doi.org/10.1038/s41576-021-00400-5

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