Cache Domain Containing 1 Polymorphism in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
Abstract number :
1.423
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1886426
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Authors :
Soomi Cho, MD - Gangnam Severance Hospital; Won-Joo Kim, MD, PhD - Professor, Neurology, Gangnam Severance Hospital; Hye Jeong Lee, MD - Neurology - Gangnam Severance Hospital
Rationale: Hippocampal sclerosis (HS) is a common neuropathological condition encountered in mesial temporal lobe epilepsy (MTLE) patients. Presence of HS is known for a predictor of poor response to treatment with antiepileptic drugs. The pathogenesis and genetic risk factors of HS are not fully characterized. There has been no prior published genome-wide association studies (GWAS) comparing MTLE with and without HS (MTLE+HS and MTLE-HS). In this present study, we report a genome-wide screen for polymorphisms associated with HS in MTLE patients.
Methods: One hundred fifty-seven adult MTLE patients were recruited from Yonsei University College of Medicine. Patient histories, electroencephalographic recordings and brain imaging studies were reviewed to include subjects whose seizure semiology and scalp EEG were consistent with MTLE. We excluded patients who had any visible epileptogenic lesion except for HS. Of 157 subjects, 52 cases were MTLE+HS and 105 cases were MTLE-HS. We performed quality control for all samples and genotyped SNPs according to protocols. The PLINK software was used to perform quality control and association analyses for imputation and replication. The quantile–quantile plot and Manhattan plot of imputation data were generated using R version 2.15.2. Regional association plotting was conducted using LocusZoom. The validation study was performed by analyzing samples for replication and then analyzing combined imputation data. Association analysis of the combined samples was performed by using the Cochran–Mantel–Haenszel test, and the Breslow–Day test was used to evaluate the heterogeneity of odds ratios for the two cohorts.
Results: After applying quality control parameters, 290,091 single-nucleotide polymorphisms (SNPs) were genotyped and used for imputation. Five candidate SNPs with an allelic χ2 P value < 1×10-6 were identified and analyzed for replication. Only one intronic variant, rs1436751, in a region of strong linkage disequilibrium encompassing cache domain containing 1 (CACHD1) was significantly associated with HS (Bonferroni-corrected P=0.043). MTLE homozygous for the risk alleles had a 3.2-fold increased susceptibility to HS (95% confidence interval 1.8 to 5.6).
Conclusions: We report one novel susceptibility locus of HS in MTLE patients. We compared MTLE+HS with MTLE-HS to cancel out the impact of other factors related to MTLE except for HS. Variation near CACHD1 may increase susceptibility to HS. Some recent research has revealed that CACHD1 is a new activity-modifying protein for voltage-gated calcium channels. CACHD1 overexpression in murine hippocampal neurons increased neuronal excitability. Larger GWAS and further studies on human CACHD1 are therefore recommended.
Funding: Please list any funding that was received in support of this abstract.: none.
Genetics