Pleiotropy of polygenic factors associated with focal and generalized epilepsy in the general population

Leu, Costin; Richardson, Tom G; Kaufmann, Tobias; Meer, Dennis van der; Andreassen, Ole A.; Westlye, Lars T.; Busch, Robyn M.; Smith, George Davey; Lal, Dennis

doi:10.1371/journal.pone.0232292

Cited by 19 publications

(23 citation statements)

References 40 publications

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“…The observation that all individuals of the cluster with the highest FE‐PRS have psychiatric comorbidities, together with the 5.33‐fold enrichment of individuals with psychiatric comorbidities in the top 5% highest FE‐PRS, may be explained by shared genetically perturbed networks and pathways between common neurological and psychiatric disorders (including epilepsy, depression, and anxiety) 16 . In agreement with this hypothesis, we recently found that high FE‐PRS is associated with psychiatric traits 17 …”

Section: Discussionsupporting

confidence: 59%

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Polygenic risk heterogeneity among focal epilepsies

et al. 2020

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Focal epilepsy (FE) has a prevalence of 2.99 in 1000 people. 1 The presentation of FE is clinically highly diverse. Cognitive impairments, such as learning and memory difficulties, and mood disorders are frequently comorbid with FE. FE can develop at any point in life, but associated etiologies vary by age, with congenital anomalies often associated with earlier seizure onset, and stroke/neurodegenerative disorders associated with older age at seizure onset. 2 Several studies have reported rare forms of FE believed to be caused by a single

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Section: Discussionsupporting

confidence: 59%

“…16 In agreement with this hypothesis, we recently found that high FE-PRS is associated with psychiatric traits. 17 Our results should be interpreted in light of several limitations. First, the FE-PRS were derived from GWAS based on individuals with European ancestry.…”

Section: Discussionmentioning

confidence: 86%

Polygenic risk heterogeneity among focal epilepsies

et al. 2020

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“…When combined, these naturally intertwined dimensions offer new insights into the pathophysiology of system-level disorders such as epilepsy 31 . Neuroimaging studies of large-scale networks can profit from studies on the landscape of genetic risk factors in common epilepsies 32,33 . Recently, the open release of postmortem human transcriptomics datasets, such as the Allen Human Brain Atlas (AHBA), has yielded opportunities to explore how gene co-expression patterns in the brain reflect macroscale neuroimaging findings 34,35 .…”

Section: Introductionmentioning

confidence: 99%

Structural network alterations in focal and generalized epilepsy follow axes of epilepsy risk gene expression: An ENIGMA study

Larivière

Royer

Rodríguez‐Cruces

et al. 2021

Preprint

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Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.

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“…Recent results indicate that some genetic risk factors are shared between common neurological and psychiatric disorders (including epilepsy, depression, anxiety, and neuroticism) 8 , 9 and may explain part of the observed phenotypic overlap 10 . Widespread pleiotropy for genes associated with Mendelian forms of neurological and psychiatric disorders suggests that these disorders are the response of a complex neurologic network, which is altered in several domains of function.…”

Section: Introductionmentioning

confidence: 99%

Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

Leu

Bautista

Sudarsanam

et al. 2020

Sci Rep

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Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ2), P = 0.30; PNES vs. epilepsy (2 × 2 χ2), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

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Pleiotropy of polygenic factors associated with focal and generalized epilepsy in the general population

Cited by 19 publications

References 40 publications

Polygenic risk heterogeneity among focal epilepsies

Polygenic risk heterogeneity among focal epilepsies

Structural network alterations in focal and generalized epilepsy follow axes of epilepsy risk gene expression: An ENIGMA study

Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

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