Identification of susceptibility variants to benign childhood epilepsy with centro-temporal spikes (BECTS) in Chinese Han population

Background: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. Methods: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. Findings: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 x 10(-8) <P< 10(-5)). Using combined genetic and brain tissue gene expression data analyzed by Summary-data-based Mendelian Randomization (SMR), causative association of BECTS was demonstrated with SNP rs1948 and the CHRNA5 t3603436 transcript (P-eqtl = 2.10 x 10(-12), P-smr = 7.9 x 10(-5)). This finding indicates rs1948 is significantly associated with BECTS through effects on expression of CHRNA5 in brain tissue. The identification of novel loci suggests involvements of KALRN and the CHRNA5-A3-B4 cluster in BECTS. Using a generalized SMR approach we demonstrate that maternal smoking around birth is significantly associated with increased risk of BECTS (odds ratio = 3.90, P = 0.0099). Interpretation: This study shows that BECTS risk is at least partially heritable and due to common genetic variants. Additionally, we demonstrate that BECTS risk is substantially increased by maternal smoking around birth. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)