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Título

Genome-wide association study in mesial temporal lobe epilepsy with hippocampal sclerosis

Resumo

Introduction: Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of spontaneous seizures initiated in the mesial temporal lobe structures. MTLE is a type of focal epilepsy frequently associated with a characteristic histopathological lesion denominated hippocampal sclerosis (HS). Many patients with MTLE+HS have severe epilepsy, which is often resistant to treatment with antiseizure medication. Recent genome-wide association metanalysis found suggestive evidence of association to two loci on chromosomes (ch)s 3q25.41 and 6q22.31 in patients with focal epilepsy and HS, and a locus on ch 2q24.3 for all focal epilepsies combined [1]; however, to our knowledge, these results have not been replicated.

Materials and Methods: We studied 501 patients and 1.146 controls. Patients with MTLE+HS were ascertained in several epilepsy centers in Brazil and Portugal. All patients fulfilled the diagnostic criteria for MTLE+HS proposed by the International League Against Epilepsy. In addition, controls were ethnically matched to patients. We used the Affymetrix 6.0 array for SNP genotyping.

Results: Principal component analyses showed no significant differences in the genomic composition of patients and controls and were used as covariates in the association study. After quality control, we used an additive model for the association to perform a logistic regression. We found four novel association signals at chs 7 (p = 5.689e-10), 9 (p = 2.68e-10), 12 (p = 2.989e-10) and ch 14 (p = 3.645e-8).

Discussion/Conclusion: The SNPs associated with the phenotype are in introns and intergenic regions, suggesting that regulatory elements are likely to be involved in the genetic predisposition to MTLE+HS. Future steps in this project aim to perform local ancestry inference and integrate transcriptomic and epigenomic data to identify putative causal variants.

Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), SP, Brazil.

Reference: [1] International League Against Epilepsy Consortium on Complex Epilepsies. Nat Commun 9(1): 5269, 2018.