Putative Susceptibility Alleles Identified From A Genome Wide Association Study in Epilepsy
Abstract number :
3.293
Submission category :
11. Human Genetics
Year :
2010
Submission ID :
13305
Source :
www.aesnet.org
Presentation date :
12/3/2010 12:00:00 AM
Published date :
Dec 2, 2010, 06:00 AM
Authors :
Russell Buono, H. Zhang, K. Wang, M. Sperling, D. Dlugos, W. Lo, P. Cossette, C. Hou, J. Glessner, J. Bradfield, P. Sleiman, Y. Guo, C. Kim, R. Chiavacci, F. Mentch, H. Qui, B. Keating, S. Grant, M. Privitera, J. French, S. Schachter, F. Lohoff, W. Berret
Rationale: To identify genetic influences on human epilepsy we performed a genome wide association study (GWAS) on DNA samples from unrelated patients with either idiopathic generalized (IGE) or cryptogenic focal (CFE) seizures compared to unrelated healthy controls. Methods: The Illumina HumanHap550 Bead Chip was used to genotype over 500,000 single nucleotide polymorphisms (SNPs) across the entire genome in a cohort of cryptogenic focal patients (n=295) and healthy controls (n=2,282). A second cohort of idiopathic generalized patients (n=412) and separate controls (n=3,876) was then genotyped on the same platform. Differences between SNP minor allele frequencies were compared between patients and controls using contingency analysis. Copy number variation (CNV) was identified using the Penn CNV software program. All subjects were of European ancestry and all studies approved by the local institutional review boards at each participating site. Results: SNP rs9572727 on Chr 13q22 near the 5 end of Dachshund 1 (DACH1) was the marker that exhibited the largest statistical difference between cases and controls: focal cohort p=0.001, OR 1.93; IGE cohort p= 3.46x10-13, OR 2.89; combined cohort p=1.71x10-14, OR 2.48. Other candidate genes include MYH11 and MMP8 for the combined cohort (p=1.3x10-9 and p=6.3x10-7 respectively) ZNF695 and VGLL3 for the focal cohort and C6orf103, ENPP2 and C7orf41 for the IGE cohort. In addition, preliminary CNV analysis identified two IGE patients that carry a 1.5 Mb deletion at 15q13.3 and two separate IGE patients that carry a 1.2 Mb deletion on 16p13.11, both CNV regions were previously associated with epilepsy. Conclusions: Our GWAS results identify several novel candidate genes for further analysis to identify potential epilepsy susceptibility alleles. These preliminary data await replication in an independent cohort and suggest that variations in genes related to developmental biology and control of gene expression may be associated with epilepsy susceptibility. In addition, we have identified CNVs on 15q13.3 and 16p13.11 in our cohort previously reported as a susceptibility factors for epilepsy. Future work will increase the size of the current cohorts and replicate these studies in independent cohorts.
Genetics