SUDEP risk is influenced by longevity genomics: a polygenic risk score study

作者：Helena Martins, James D. Mills, Susanna Pagni, Medine I. Gulcebi, Angeliki Vakrinou, Patrick B. Moloney, Lisa M. Clayton, Ravishankara Bellampalli, Hannah Stamberger, Sarah Weckhuysen, Pasquale Striano, Federico Zara, Richard D. Bagnall, Rebekah V. Harris, Kate Lawrence, Lynette G. Sadleir, Douglas E. Crompton, Daniel Friedman, Juliana Laze, Ling Li, Samuel F. Berkovic, Christopher Semsarian, Ingrid E. Scheffer, Orrin Devinsky, Karoline Kuchenbaecker, Simona Balestrini, Sanjay M. Sisodiya · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105841 · 被引用次数：4 · 研究领域：Epilepsy research and treatment、Genomics and Rare Diseases、Genetic Associations and Epidemiology

BACKGROUND: Sudden Unexpected Death in Epilepsy (SUDEP) is a rare and tragic outcome in epilepsy, identified by those with the condition as their most serious concern. Although several clinical factors are associated with elevated SUDEP risk, mechanisms underlying SUDEP are poorly understood, making individual risk prediction challenging, especially early in the disease course. We hypothesised that common genetic variation contributes to SUDEP risk. METHODS: Genetic data from people who had succumbed to SUDEP was compared to data from people with epilepsy who had not succumbed to SUDEP and from healthy controls. Polygenic risk scores (PRSs) for longevity, intelligence and epilepsy were compared across cohorts. Reactome pathways and gene ontology terms implicated by the contributing single nucleotide polymorphisms (SNPs) were explored. In the subset of SUDEP cases with the necessary data available, a risk score was calculated using an existing risk prediction tool (SUDEP-3); the added value to this prediction of SNP-based genomic information was evaluated. FINDINGS: Only European-ancestry participants were included. 161 SUDEP cases were compared to 768 cases with epilepsy and 1153 healthy controls. PRS for longevity was significantly reduced in SUDEP cases compared to disease (P = 0·0096) and healthy controls (P = 0·0016), as was PRS for intelligence (SUDEP cases compared to disease (P = 0·0073) and healthy controls (P = 0·00024)). The PRS for epilepsy did not differ between S...