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Polygenic risk heterogeneity among focal epilepsies
Author(s) -
Gramm Marie,
Leu Costin,
PérezPalma Eduardo,
Ferguson Lisa,
Jehi Lara,
Daly Mark J.,
Najm Imad M.,
Busch Robyn M.,
Lal Dennis
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16717
Subject(s) - genetic heterogeneity , genome wide association study , genetic association , etiology , polygenic risk score , meta analysis , epilepsy , cluster (spacecraft) , population , genetic variants , medicine , biology , genetics , phenotype , single nucleotide polymorphism , psychiatry , genotype , gene , environmental health , programming language , computer science
Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score “FE‐PRS” that combines small effect sizes of thousands of common variants from the largest FE‐GWAS (genome‐wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE‐PRS compared to 20 435 matched population controls and observed heterogeneous FE‐PRS burden among the subgroups. The highest phenotypic variance explained by FE‐PRS was identified in a cluster analysis–defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better‐powered FE‐PRS might have clinical utility.