Genetic risk, antiseizure medications, and lifestyle factors in epilepsy-associated obesity and overweight

Jiaqi Wang; Zihua He; Sisi Shen; Tong Yi; Shengyi Liu; Quan Yang; Josemir W Sander; Dong Zhou; Xiutian Sima; Jinmei Li

doi:10.1038/s41366-026-02069-4

Genetic risk, antiseizure medications, and lifestyle factors in epilepsy-associated obesity and overweight

Int J Obes (Lond). 2026 Apr 6. doi: 10.1038/s41366-026-02069-4. Online ahead of print.

Authors

Jiaqi Wang^#¹, Zihua He^#¹, Sisi Shen¹, Tong Yi¹, Shengyi Liu¹, Quan Yang¹, Josemir W Sander^{1

2}, Dong Zhou¹, Xiutian Sima³, Jinmei Li⁴

Affiliations

¹ Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
² UCL Queen Square Institute of Neurology, London WC1N 3BG & Chalfont Centre for Epilepsy, Chalfont St Peter, Buckinghamshire, UK.
³ Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China. simaxiutian@scu.edu.cn.
⁴ Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. lijinmei@wchscu.cn.

^# Contributed equally.

PMID: 41942740
DOI: 10.1038/s41366-026-02069-4

Abstract

Background: Obesity is common among people with epilepsy and is influenced by genetic susceptibility, lifestyle behaviours, and antiseizure medications (ASMs). How ASMs and lifestyle factors interact with genetic risk for obesity in epilepsy remains unclear.

Methods: This population-based cohort study analysed UK Biobank participants with epilepsy recruited between 2006 and 2010. Polygenic risk scores for body mass index (PRS_BMI) classified individuals into low, medium, and high genetic risk groups. Associations between commonly used ASMs-including lamotrigine (LTG), valproate (VPA), carbamazepine (CBZ), and levetiracetam (LEV)-and overweight/obesity were examined using multivariable logistic regression, adjusting for demographic, socio-economic, and lifestyle factors. Gene-drug interactions were assessed, and Mendelian randomisation (MR) was used to explore potential links between LTG target gene expression and BMI.

Results: A total of 8451 individuals were included. In multivariable logistic regression analyses, LTG use was associated with lower odds of obesity (OR = 0.63, 95% CI: 0.47-0.85, P = 0.002) and overweight (OR = 0.72, 95% CI: 0.56-0.92, P = 0.014). VPA was associated with an increased obesity risk (OR = 1.31, 95% CI: 1.07-1.60, P = 0.010). Subgroup analysis suggested that LTG use was associated with a lower risk of obesity, particularly among individuals with low to moderate PRS_BMI. As PRS_BMI increased, the absolute difference in overweight risk between LTG users and non-users decreased. Sex-stratified analyses showed that LTG had a more substantial protective effect in males, while VPA was more strongly associated with obesity risk in females. Lifestyle factors were significantly associated with obesity and overweight risk, with higher physical activity levels and adherence to a healthy diet being associated with lower risk. MR analysis suggested a potential causal relationship between LTG target gene expression and BMI.

Conclusions: Genetic predisposition, ASMs, and lifestyle behaviours were collectively associated with the risk of overweight and obesity in epilepsy. LTG use was associated with a lower risk of weight gain, particularly among individuals with lower genetic susceptibility, with this association attenuating as genetic risk for obesity increased. VPA was associated with an increased risk of obesity, especially in females. These findings support personalised metabolic risk management in epilepsy care.