Women’s Reproductive Traits and Epilepsy: A Two-sample Mendelian Randomization Study
Abstract number :
3.357
Submission category :
4. Clinical Epilepsy / 4E. Women's Issues
Year :
2024
Submission ID :
431
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Lu Zhang, MD, PhD – Huashan Hospital
Yuncan Chen, PhD – Department of Neurology, Huashan Hospital, Fudan University
Shimin Xu, MD,PhD – Department of Neurology, Huashan Hospital, Fudan University
Ye Xu, MD,PhD – Huashan Hospital
Xunyi Wu, MD, PhD – Department of Neurology, Huashan Hospital, Fudan University
Rationale: Numerous epidemiological studies have shown a close relationship between women's reproductive traits and the etiology of various forms of epilepsy. However, there was still insufficient evidence supporting their direct causality effect. We conducted a two-sample Mendelian randomization (MR) study to investigate the association between age at menarche (AAM), age at natural menopause (ANM), age at first birth (AFB), and the risk of various phenotypes of epilepsy.
Methods: Genetic instruments were obtained from the hitherto largest genome-wide association studies (GWAS) conducted in AAM (N = 329,345), ANM (N = 143,819), AFB (N = 542,901), and epilepsy (Ncase = 29,944, Ncontrol = 52,538), all of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy, focal epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized epilepsy with tonic-clonic seizures (GTCS), focal epilepsy with hippocampal sclerosis (focal HS), focal epilepsy with other lesions, and lesion-negative focal epilepsy. The causal relationship was examined through different MR approaches, and the inverse variance weighted estimates were reported as the main results. MR-Egger, MR-PRESSO, and weighted median methods supplemented the sensitivity analysis. Also, the horizontal pleiotropy was detected by the MR-Egger intercept and MR-PRESSO methods, while the heterogeneity was assessed using Cochran’s Q statistics.
Results: There was strong evidence that genetically predicted later AAM was linked to a lower risk of both CAE (OR, 0.63; 95% CI, 0.52–0.78; P< 0.01) and JAE (OR, 0.59; 95% CI, 0.42–0.85; P< 0.01). Furthermore, genetically determined later AFB has a reduced risk of all epilepsy (OR = 0.70, 95% CI = 0.62–0.85, P < 0.001), focal epilepsy (OR = 0.93, 95% CI = 0.84–0.99, P< 0.01), and generalized epilepsy (OR = 0.97, 95% CI = 0.94–0.99, P< 0.01). For epilepsy due to potential structural abnormalities, such as focal epilepsy with hippocampal sclerosis, we didn’t find significant roles played by women's reproductive traits.
Conclusions: These findings revealed a direct association between age at menarche and two forms of idiopathic generalized epilepsy (CAE and JAE). Future studies are warranted to explore underlying pathomechanisms, such as hormonal levels, that are responsible for these associations. A later age at first birth and an overall decreased risk in epilepsy indicate some hidden socioeconomic factors to be explored. For phenotypes with a rather clear structural etiology, women's reproductive traits are less likely to be involved in the disease's development.
Funding: This work was supported by grants from the National Key R&D Program of China (2022YFC2503803).
Clinical Epilepsy