Genome-Wide Insights and Polygenic Risk Scores in Common Epilepsies: A Narrative Review

The research of single gene-related disorders or pathogenic copy-number variations (CNVs) has given a significant impetus to the shift from a diagnostic work-up focused on epileptic syndromes to genomic approaches in individuals with severe pediatric-onset epilepsies and in developmental and epileptic encephalopathies. Genome-wide association studies (GWAS) have identified various loci of susceptibility for common epilepsies and highlighted a strong predisposing role of common variants in several genes involved in well-known monogenic diseases. The largest GWAS identified eight major loci with stronger genome-wide significance for epilepsy, regardless the underlying epileptic syndrome: 2q24.3, 2p16.1, 4p15.1, 7q21.11, 8p23.1, 9q21.13, 10q24.32, 16q12.1, 2p16.1 and 2q24.3 occurred more frequently in patients with genetic generalized epilepsies. Loci 4p12, 8q23.1 and 16p11.2 achieved a high genome-wide significance for Juvenile Myoclonic Epilepsy. Childhood Absence Epilepsy was significantly genome-wide associated with 2p16.1 and 2q22.3. The loci 3q25.31, 6q22.31 and 2q24.3 were significantly associated with non-acquired focal epilepsies. Polygenic risk scores (PRS) are used to quantify the cumulative effects of several common genetic variants in a single score, each of which individually contributes minimally to disease susceptibility. The impact of PRS on clinical practice might be relevant for epilepsy risk prediction in groups of patients at high risk of developing epilepsy in the near future. Elevated PRS values have been observed in genetic generalized epilepsies particularly in familial forms, females, and patients with previous seizure events. Among comorbidities associated with epilepsy, depression, psychosis, and attention-deficit/hyperactivity disorder (ADHD) showed significantly elevated PRS.