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Epidemiology and Population Health

Age-specific childhood obesity and adult cholelithiasis: association and shared transcriptomic bases

International Journal of Obesity (2025)Cite this article

Subjects

Abstract

Objectives

The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, the biological basis for the association between childhood obesity and adult cholelithiasis is poorly understood, which poses a challenge for preventing adult cholelithiasis in specific biological pathways.

Methods

Summary statistics of genome-wide association studies (GWASs) of childhood age-specific body mass index (BMI) at 12 time points and adult cholelithiasis derived from FinnGen were used in this study, with the former covering data from birth to 8 years. Linkage disequilibrium score regression (LDSC) analyses were used to assess the genetic correlations of age-specific childhood BMI to cholelithiasis. Two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses were utilized to explore the causal associations. As downstream analyses, summary-based Mendelian randomization (SMR) analyses, transcriptome-wide association studies (TWAS), and Bayesian colocalization were conducted to discover the shared transcriptomic signals. The GWAS summary statistics of cholelithiasis from the UK Biobank were used for sensitivity analyses.

Results

LDSC analyses revealed significant genetic correlations between 11 age-specific childhood BMIs and adult cholelithiasis (except for birth BMI). Two-sample MR and MVMR analyses indicated causal relationships between birth BMI and BMI at 8 months, 1.5 years, 7 years, and 8 years after birth and adult cholelithiasis. SMR, TWAS, and colocalization analyses identified MLXIPL as the strongest overlapping signal between age-specific BMI and adult cholelithiasis.

Conclusion

This study provides new evidence on the relationships between childhood obesity and adult cholelithiasis, highlighting the role of early intervention for obesity in childhood at key time points. MLXIPL gene expression was identified as a potential biological pathway, suggesting potential therapeutic targets and precise intervention strategies for childhood obesity and adult cholelithiasis.

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Fig. 1: Study design.
Fig. 2: Genetic correlations between 12 age-specific childhood BMIs and adult cholelithiasis.
Fig. 3: Causal associations between 12 age-specific childhood BMIs and adult cholelithiasis revealed by the IVW or the Wald ratio method.
Fig. 4: The colocalization results of PPH4 ≥ 0.75 using GWAS and eQTL data in esophageal mucosal tissue.

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Data availability

GWAS summary statistics for 12 age-specific BMIs are available at: https://www.fhi.no/en/studies/moba/for-forskere-artikler/gwas-data-from-moba/. GWAS summary statistics for cholelithiasis from the FinnGen is available at: https://finngen.gitbook.io/documentation. GWAS summary statistics for cholelithiasis from the UKB is available at: https://www.leelabsg.org/resources. GWAS summary statistics for adolescent BMI is available at: EGG (Early Growth Genetics) Consortium. The eQTL summary data for GTEx are available at: https://yanglab.westlake.edu.cn/software/smr/#DataResource. The eQTL summary data for eQTLGen Consortium is available at: https://eqtlgen.org/cis-eqtls.html.The tissue weights for GTEx are available at: http://gusevlab.org/projects/fusion/.

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Acknowledgements

We express our gratitude to the patients and investigators who have contributed to MoBa Cohort, the FinnGen Consortium, the UK Biobank (UKB), the Genotype-Tissue Expression Project (GTEx), the eQTLGen Consortium and the Early Growth Genetics Consortium.

Funding

This study was supported by the Sichuan Provincial Science and Technology Support Program (2023YFH0097, Yu Tong).

Author information

Authors and Affiliations

  1. Department of Maternal and Child Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Lihua Liu, Lu Zhang, Yiwen Liao, Xin Jin, Yunzhu Chen, Tian Yang, Xingxing Li, Yuheng Cao, Chuan Yu, Chenghan Xiao & Zhenmi Liu

  2. Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

    Lu Zhang & Zhenmi Liu

  3. West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, China

    Yu Tong

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  1. Lihua Liu
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Contributions

Lihua Liu, Writing - original draft, Conceptualization, Formal analysis, Validation. Lu Zhang, Supervision, Writing –review & editing. Yiwen Liao, Formal analysis, Investigation. Xin Jin, Resources, Validation. Yunzhu Chen, Resources, Software. Tian Yang, Visualization. Xingxing Li, Supervision. Yuheng Cao, Validation. Chuan Yu, Supervision. Chenghan Xiao, Methodology, Conceptualization. Zhenmi Liu, Writing - review & editing, Supervision. Yu Tong, Writing –review & editing, Supervision. All authors reviewed and approved the manuscript.

Corresponding authors

Correspondence to Chenghan Xiao, Zhenmi Liu or Yu Tong.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study adheres to the STROBE-MR guidelines. Each included GWAS was conducted with institutional review board approval and informed participant consent. The MoBa study protocol was approved by the administrative board of the Norwegian Institute of Public Health, with data collection authorized by the Norwegian Data Protection Agency and the Regional Committee for Medical Research Ethics (approval number: 2012/67). The UK Biobank received ethics approval from the North West Multi-Centre Research Ethics Committee. The FinnGen GWAS data were approved by the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS; approval number: HUS/990/2017). The GWAS data for adolescent BMI from the EGG Consortium were obtained from ethically approved studies, with each contributing cohort receiving approval from its respective local ethics committee. Other datasets used (GTEx, eQTLGen, and tissue weight data) are publicly available summary-level data generated from studies conducted under appropriate ethical approvals and informed consent. No new ethical approval was required for this analysis.

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Liu, L., Zhang, L., Liao, Y. et al. Age-specific childhood obesity and adult cholelithiasis: association and shared transcriptomic bases. Int J Obes (2025). https://doi.org/10.1038/s41366-025-01877-4

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