A genome-wide association study of symptomatic epilepsy in Han Chinese detects multiple variants

Abstract

Epilepsy is one of the most common serious neurological disorders, affecting approximately 1% of the population. While idiopathic epilepsy has been the most studied form and has the most evidence for genetic influence, there has also been converging evidence for genetic influences on the more common symptomatic form, where the epilepsy is a result of a known brain injury or lesion. We conducted a genome-wide association study (GWAS) of 504 symptomatic epilepsy cases and a cohort of shared control samples of 1947 subjects participating in several GWAS of complex disease and an additional 1000 healthy individuals. All cases and controls were Han Chinese. We employed the Illumina HumanHap 610-Quad platform, which assays approximately 600,000 SNPs. From analysis of this initial GWAS, we identified three loci containing variants that confer epilepsy risk, in addition to confirming a previously known association with the GRIK2 gene. One of the loci (rs4853352, p < .000002) on chromosome 2p12 was intragenic but near neural developmental genes, including LRRTM1 and LRRTM4 (SLIT proteins), which may play a role in the development and maintenance of the vertebrate nervous system. At 13q31.1, a genome-wide significant SNP (rs9519914, p < .000000005) is near the SLITRK6 gene, a member of the integral membrane proteins with 2 N-terminal leucine-rich repeat (LRR) domains similar to those of SLIT proteins, which is expressed predominantly in neural tissues and has neurite-modulating activity. The strongest signal (rs12148329, p < .00000000002) is in the intronic region of the FAM108C1 gene on chromosome 15q25.1, which is expressed in human atherosclerotic lesions and significantly elevated in patients with unstable angina. These SNPs and approximately 70 others are being replicated in a larger independent sample of Chinese epilepsy patients and controls.