Evaluation of the Role of Common Variant Burden in the Familial Aggregation of Epilepsy
Abstract number :
3.347
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1826260
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Victoria Smuk, BS - Genomic Medicine Institute & Epilepsy Center, Cleveland Clinic; Costin Leu - Genomic Medicine Institute & Epilepsy Center, Cleveland Clinic; Javier López-Rivera - Genomic Medicine Institute & Epilepsy Center, Cleveland Clinic; Lisa Ferguson - Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland; Lara Jehi - Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland; Imad Najm - Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland; Robyn Busch - Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland; Dennis Lal - Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland
Rationale: Polygenic risk scores (PRS) have proven to help predict the genetic risk of developing a disease phenotype. We previously showed that common genetic risk associated with epilepsy is significantly enriched in patients with focal and generalized epilepsy. For several neurological disorders such as schizophrenia, migraine, and autism, it has been shown that patients with a known family history of the disease carry a significantly higher polygenic risk than those with no family history. However, the relationship between family history and the polygenic burden has not been established for epilepsy. Our aim was to quantify the genetic burden in epilepsy cohorts to assess if the genetic risk is further enriched in cases of familial epilepsy.
Methods: Using genome-wide genotyping data generated with the Illumina Global Screening Array-24 with Multi-disease drop-in (GSA-MD v1.0), we quantified the common genetic burden in individuals with FE or GE from a single clinical center, the Cleveland Clinic Epilepsy Center. Quality-filtered genotyping data of all individuals was imputed to the TOPMed Reference panel r2 using Minimac4 and reference-based phasing with Eagle-v2.4, as implemented on the TOPMed Imputation server. PRS were derived from summary statistics of the ILAE Consortium on Complex Epilepsies European ancestry GWAS for generalized and focal epilepsy.
Results: After quality control, we identified 336 individuals of European ancestry with FE or GE and a known family history of epilepsy (FE, 40 out of 289 individuals with FE and at least one first-degree relative; GE, 15 out of 47 individuals). Overall, we found that individuals with FE or GE and first-degree relatives with epilepsy had higher FE-PRS or GE-PRS, respectively than individuals without a family history. At the time of the conference, we will present the results of a validation cohort and the combined cohort of all individuals with FE or GE and a known family history of epilepsy.
Conclusions: Our findings demonstrate that common polygenic risk for epilepsy contributes to the familial aggregation of epilepsy. Thus, our results could be used to inform future genetic studies with a specific focus on familial cases.
Funding: Please list any funding that was received in support of this abstract.: This work was supported by institutional funding from the Cleveland Clinic Foundation. RMB received support from the NIH/NCATS, CTSA UL1TR000439, Cleveland, Ohio.
Genetics