Analiza obciążenia genetycznego u 748 879 osób identyfikuje związek kompleksu białkowego LGI1-ADAM23 z epilepsją
Gene burden meta-analysis of 748 879 individuals identifies LGI1-ADAM23 protein complex association with epilepsy
W skrócie
Badacze przeanalizowali dane genetyczne ponad 750 tysięcy osób z trzech dużych biobanków i odkryli, że mutacje w genach LGI1 i ADAM23 są związane z ryzykiem epilepsji. Wyniki pokazują, że geny te mogą się zaangażować w epilepsję poprzez wzajemne oddziaływanie białek, a inne odkryte geny mogą wpływać na szersze zaburzenia neurologiczne i zdrowotne. Badanie dowodzi, że analiza danych genetycznych z dużych populacji może pomóc w zrozumieniu przyczyn epilepsji i w przyszłości przyczynić się do lepszego leczenia tej choroby.
Oryginalny abstract (angielski)
Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through clinical or research settings. Recent biobank-based approaches, leveraging large-scale population datasets, offer opportunities to explore genetic associations in broader epilepsy phenotypes, including milder, later onset forms. We analyzed data from more than 750 000 individuals across the UK Biobank, All of Us, and Massachusetts General Brigham Biobank, including 20 026 individuals with epilepsy. Rare coding variant burden testing revealed a significant association with LGI1, a known epilepsy gene. Among the other top 10 associated genes, seven had prior evidence linking them to epilepsy (GABRG2, ATP1A3), neurological disorders with comorbid seizures (HTRA2, KRIT1, STAG1), possible involvement in seizure phenotypes (ADAM23), or roles in neuronal function (PDCD4). Thus, we provide the first statistical evidence for ADAM23 as a candidate gene for epilepsy, based on the suggestive association signal combined with prior biological evidence from both animal (canine and murine) and one recent human epilepsy case study, potentially contributing to human epilepsy through its direct interaction with LGI1. Phenome-wide analyses highlighted the pleiotropic effects of epilepsy genes, with LGI1 and ADAM23 predominantly associated with epilepsy, whereas other genes such as KRIT1, TSC1, and TSC2 exhibited broader systemic involvement. Our study shows the potential of population-scale genomic data and suggests that integrating these datasets with deep phenotyping will uncover more novel insights into epilepsy genetics in the future.