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. 2025 Jul 16.
doi: 10.1249/MSS.0000000000003815. Online ahead of print.

Genetic Determinants of Leisure-Time Physical Activity in the Taiwanese Population: A Genome-Wide Association Study

Lung-An Hsu  1 , Semon Wu  2 , Ngoc Yen Tran  3 , Hsin-Hua Chou, Yu-Lin Ko
Affiliations

Genetic Determinants of Leisure-Time Physical Activity in the Taiwanese Population: A Genome-Wide Association Study

Lung-An Hsu et al. Med Sci Sports Exerc. .

Abstract

Background: Physical inactivity contributes to systemic disease burden and premature mortality worldwide. Leisure-time physical activity (LTPA) improves health outcomes; however, its genetic determinants, particularly in Asian populations, remain unclear. This study aimed to identify genetic loci associated with LTPA in the Taiwanese population.

Methods: We conducted genome-wide association studies (GWASs) in 122,258 Taiwan Biobank participants. LTPA was assessed both as a binary trait (regular exerciser vs. non-exerciser) and an ordinal trait (categorized by MET-hours/week into low, moderate, and high PA levels). Logistic and ordinal logistic regression models were used under an additive genetic model, adjusting for age, age 2 , sex, BMI, smoking, and the first 10 genetic principal components. Candidate nonsynonymous mutations were further examined in 1,494 whole-genome sequenced participants.

Results: Binary trait GWAS identified genome-wide significant (GWS) loci at ATXN2 (12q24.12), FTO (16q12.2), and NOTCH4 (6p21.32), with associations for FTO and NOTCH4 only observed in BMI-adjusted models. Ordinal trait analysis (MET-hours/week <10, 10-<20, ≥20) identified a single GWS locus at BRAP (12q24.12). Fine-mapping of 12q24.12 revealed multiple GWS single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium (LD) with lead variants; these signals largely disappeared after conditional analysis, consistent with a single underlying association. Whole-genome sequencing and LD analysis identified three GWS nonsynonymous mutations, with ALDH2 rs671 emerging as the most likely causal variant.

Conclusions: ATXN2-ALDH2 region on chromosome 12q24.12 was identified as a key locus for LTPA in Taiwanese individuals. These findings enhance our understanding of the genetic basis of physical activity and may inform future precision medicine and public health strategies.

Keywords: GENOME-WIDE ASSOCIATION STUDY; LEISURE-TIME PHYSICAL ACTIVITY.

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Conflict of interest statement

Conflict of Interest and Funding Source: Financial support for this study was provided through grants from the National Science and Technology Council (NSTC 112-2314-B-303-023-MY3, NSTC 113-2314-B-303-011), Buddhist Tzu Chi Medical Foundation (TCMF-EP 111-02) to Y. L. Ko, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TCRD-TPE-112-RT-1) to H. H. Chou and the National Science and Technology Council (NTSC 113-2314-B-182-016) to L. A. Hsu. We greatly appreciate the technical support of the Core Laboratory of the Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, the expert statistical analysis assistance from Tsung-Han Hsieh, and the bioinformatics support from Kimforest LTD, Taiwan.

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