Polygenic overlap of physical activity with schizophrenia and Parkinson's disease
- 1University of Cape Town
Abstract
Physical activity levels are increasingly investigated as candidate digital biomarkers across a range of psychiatric and neurological disorders. Physical activity is heritable, with associated genetic variants implicating genes expressed in the central nervous system. However, its shared genetic architecture with disorders such as schizophrenia and Parkinson's disease (PD) remains poorly understood. Here, we applied complementary genome-wide methods to investigate the genetic overlap between physical activity and these disorders. We used a genome-wide association study (GWAS) of objectively measured physical activity (n = 89,683), enhanced through multi-trait GWAS incorporating self-reported activity measures (n = 124,842-377,234). In cross-trait analysis with recent GWAS of schizophrenia (n = 53,386 cases, 77,258 controls) and PD (63,555 cases, 17,700 proxy cases, and 1,746,386 controls), we find that while genetic correlations are negligible (rg=-0.02-0.02, p>0.05), polygenic overlap was substantial, with the majority of trait-influencing variants shared between the three traits. This contrast reflects mixed effect directions, which we show through convergent results from causal mixture modelling, local genetic correlations, and conjunctional false discovery rate analysis. Genes shared between activity and schizophrenia were differentially expressed in the amygdala and several basal ganglia structures, and associated with a range of cognitive-affective traits. In contrast, genes shared between activity and PD were largely associated with neurodegenerative disorders and structural brain phenotypes. Together, these findings suggest that activity draws on genes involved in motor, cognitive, affective and neurodegenerative processes, providing a genetic basis for its alteration across diverse neuropsychiatric disorders.
Related
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BibTeX
@misc{walt2026polygenic,
title = {{Polygenic overlap of physical activity with schizophrenia and Parkinson's disease}},
author = {K. van der Walt and A. Shadrin and M. Tesfaye and D. van der Meer and O. Andreassen and J. Rokicki and M. Campbell},
howpublished = {medRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.23.26356304},
url = {https://www.medrxiv.org/content/10.64898/2026.06.23.26356304v2},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Polygenic overlap of physical activity with schizophrenia and Parkinson's disease
AU - K. van der Walt
AU - A. Shadrin
AU - M. Tesfaye
AU - D. van der Meer
AU - O. Andreassen
AU - J. Rokicki
AU - M. Campbell
PY - 2026
DA - 2026/06/23
PB - medRxiv
DO - 10.64898/2026.06.23.26356304
UR - https://www.medrxiv.org/content/10.64898/2026.06.23.26356304v2
AB - Physical activity levels are increasingly investigated as candidate digital biomarkers across a range of psychiatric and neurological disorders. Physical activity is heritable, with associated genetic variants implicating genes expressed in the central nervous system. However, its shared genetic architecture with disorders such as schizophrenia and Parkinson's disease (PD) remains poorly understood. Here, we applied complementary genome-wide methods to investigate the genetic overlap between physical activity and these disorders. We used a genome-wide association study (GWAS) of objectively measured physical activity (n = 89,683), enhanced through multi-trait GWAS incorporating self-reported activity measures (n = 124,842-377,234). In cross-trait analysis with recent GWAS of schizophrenia (n = 53,386 cases, 77,258 controls) and PD (63,555 cases, 17,700 proxy cases, and 1,746,386 controls), we find that while genetic correlations are negligible (rg=-0.02-0.02, p>0.05), polygenic overlap was substantial, with the majority of trait-influencing variants shared between the three traits. This contrast reflects mixed effect directions, which we show through convergent results from causal mixture modelling, local genetic correlations, and conjunctional false discovery rate analysis. Genes shared between activity and schizophrenia were differentially expressed in the amygdala and several basal ganglia structures, and associated with a range of cognitive-affective traits. In contrast, genes shared between activity and PD were largely associated with neurodegenerative disorders and structural brain phenotypes. Together, these findings suggest that activity draws on genes involved in motor, cognitive, affective and neurodegenerative processes, providing a genetic basis for its alteration across diverse neuropsychiatric disorders.
ER -