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Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies.

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Title: Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies.
Authors: Ellis, Colin A. (AUTHOR), Ottman, Ruth (AUTHOR), Epstein, Michael P. (AUTHOR), Berkovic, Samuel F. (AUTHOR), Oliver, Karen L. (AUTHOR)
Source: Epilepsia (Series 4). Jun2025, Vol. 66 Issue 6, p2036-2045. 10p.
Subjects: Epilepsy, Monogenic & polygenic inheritance (Genetics), Heredity, Phenotypic plasticity, Genetic variation, Partial epilepsy
Abstract: Objective: Although previous research shows that generalized and focal epilepsies have at least some distinct genetic influences, it remains uncertain why some families manifest both types of epilepsy. We tested two hypotheses: (1) families with both generalized and focal epilepsy carry separate risk alleles for both types; and (2) within mixed families, the type of epilepsy each individual manifests is influenced by the relative burden of separate risk alleles for generalized epilepsies and focal epilepsies. Methods: The Epi4K cohort included 711 individuals with epilepsy from 257 families (113 generalized families, 66 focal families, 78 mixed families). We calculated polygenic risk scores (PRSs) for genetic generalized epilepsy (GGE_PRS) and for focal epilepsy (Focal_PRS). We used mixed‐effects models to compare these PRSs between and within families, accounting for relatedness. Results: Compared to population controls, individuals in generalized families had elevated GGE_PRS (p <.001) but not elevated Focal_PRS (p =.50); focal family individuals had elevated Focal_PRS (p =.008) but not elevated GGE_PRS (p =.22); and individuals in mixed families had both elevated GGE_PRS and elevated Focal_PRS (both p <.001). Within mixed families, GGE_PRS was higher in individuals with generalized epilepsy than in individuals with focal epilepsy (p <.001), whereas we did not detect a difference in Focal_PRS between individuals with generalized and focal epilepsy (p =.46). The GGE_PRS value explained 10% of the variance in phenotype within mixed families. Significance: The occurrence of families with both generalized and focal epilepsy in separate individuals is explained at least partly by the chance co‐occurrence of distinct genetic risk alleles for generalized and focal epilepsies. Within mixed families, an individual's epilepsy type can be explained at least in part by the relative burden of risk alleles for genetic generalized epilepsy. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies.
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  Data: &lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Ellis%2C+Colin+A%2E%22&quot;&gt;Ellis, Colin A.&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Ottman%2C+Ruth%22&quot;&gt;Ottman, Ruth&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Epstein%2C+Michael+P%2E%22&quot;&gt;Epstein, Michael P.&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Berkovic%2C+Samuel+F%2E%22&quot;&gt;Berkovic, Samuel F.&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Oliver%2C+Karen+L%2E%22&quot;&gt;Oliver, Karen L.&lt;/searchLink&gt; (AUTHOR)
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22Epilepsia+%28Series+4%29%22&quot;&gt;Epilepsia (Series 4)&lt;/searchLink&gt;. Jun2025, Vol. 66 Issue 6, p2036-2045. 10p.
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  Data: &lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Epilepsy%22&quot;&gt;Epilepsy&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Monogenic+%26+polygenic+inheritance+%28Genetics%29%22&quot;&gt;Monogenic &amp; polygenic inheritance (Genetics)&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Heredity%22&quot;&gt;Heredity&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Phenotypic+plasticity%22&quot;&gt;Phenotypic plasticity&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Genetic+variation%22&quot;&gt;Genetic variation&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Partial+epilepsy%22&quot;&gt;Partial epilepsy&lt;/searchLink&gt;
– Name: Abstract
  Label: Abstract
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  Data: Objective: Although previous research shows that generalized and focal epilepsies have at least some distinct genetic influences, it remains uncertain why some families manifest both types of epilepsy. We tested two hypotheses: (1) families with both generalized and focal epilepsy carry separate risk alleles for both types; and (2) within mixed families, the type of epilepsy each individual manifests is influenced by the relative burden of separate risk alleles for generalized epilepsies and focal epilepsies. Methods: The Epi4K cohort included 711 individuals with epilepsy from 257 families (113 generalized families, 66 focal families, 78 mixed families). We calculated polygenic risk scores (PRSs) for genetic generalized epilepsy (GGE_PRS) and for focal epilepsy (Focal_PRS). We used mixed‐effects models to compare these PRSs between and within families, accounting for relatedness. Results: Compared to population controls, individuals in generalized families had elevated GGE_PRS (p &lt;.001) but not elevated Focal_PRS (p =.50); focal family individuals had elevated Focal_PRS (p =.008) but not elevated GGE_PRS (p =.22); and individuals in mixed families had both elevated GGE_PRS and elevated Focal_PRS (both p &lt;.001). Within mixed families, GGE_PRS was higher in individuals with generalized epilepsy than in individuals with focal epilepsy (p &lt;.001), whereas we did not detect a difference in Focal_PRS between individuals with generalized and focal epilepsy (p =.46). The GGE_PRS value explained 10% of the variance in phenotype within mixed families. Significance: The occurrence of families with both generalized and focal epilepsy in separate individuals is explained at least partly by the chance co‐occurrence of distinct genetic risk alleles for generalized and focal epilepsies. Within mixed families, an individual&#39;s epilepsy type can be explained at least in part by the relative burden of risk alleles for genetic generalized epilepsy. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: &lt;i&gt;Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
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    Identifiers:
      – Type: doi
        Value: 10.1111/epi.18348
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 10
        StartPage: 2036
    Subjects:
      – SubjectFull: Epilepsy
        Type: general
      – SubjectFull: Monogenic & polygenic inheritance (Genetics)
        Type: general
      – SubjectFull: Heredity
        Type: general
      – SubjectFull: Phenotypic plasticity
        Type: general
      – SubjectFull: Genetic variation
        Type: general
      – SubjectFull: Partial epilepsy
        Type: general
    Titles:
      – TitleFull: Phenotypic heterogeneity in familial epilepsies is influenced by polygenic risk for generalized and focal epilepsies.
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            NameFull: Ellis, Colin A.
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            NameFull: Ottman, Ruth
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            NameFull: Epstein, Michael P.
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            – D: 01
              M: 06
              Text: Jun2025
              Type: published
              Y: 2025
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              Value: 66
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            – TitleFull: Epilepsia (Series 4)
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