Polygenic Risk Scores Shed Light on SUDEP Susceptibility

SUDEP risk is influenced by longevity genomics: A polygenic risk score study Martins H, Mills JD, Pagni S, Gulcebi MI, Vakrinou A, Moloney PB, Clayton LM, Bellampalli R, Stamberger H, Weckhuysen S, Striano P, Zara F, Bagnall RD, Harris RV, Lawrence KM, Sadleir LG, Crompton DE, Friedman D, Laze J, Li L, Berkovic SF, Semsarian C, Scheffer IE, Devinsky O, Kuchenbaecker K, Balestrini S, Sisodiya SM. EBioMedicine. 2025 Aug;118:105841. doi: 10.1016/j.ebiom.2025.105841. Epub 2025 Jul 28. PMID: 40731221; PMCID: PMC12368338. 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 SUDEP cases and disease controls (P =0.76). SNP-determined pathway and gene ontology analysis highlighted those related to inter-neuronal communication as amongst the most enriched in SUDEP. Addition of PRS for longevity and intelligence to SUDEP-3 scores improved risk prediction in a subset of cases (38) and controls (703), raising the area-under-the-curve in a receiver-operator characteristic from 0·699 using SUDEP-3 alone to 0·913 when PRSs were added. Interpretation: Common genetic variation contributes to SUDEP risk, offering new approaches to improve risk prediction and to understand underlying mechanisms.