Identification of biological functions of risk loci associated with complex epilepsy: An in-silico approach for data analysis
Paper Details
Identification of biological functions of risk loci associated with complex epilepsy: An in-silico approach for data analysis
Abstract
Complex epilepsy is caused by the interaction of multiple genes and environmental factors with number of susceptibility loci in human genome. In this study, we selected 32 epilepsy associated risk Single Nucleotide Polymorphisms (SNPs) from six published Genome Wide Association Studies (GWAS) and used online SNAP tool to deduce 288 proxy SNPs based on linkage disequilibrium. These results were then used as input data for Regulome DB; software for interpretation of regulatory variants in the human genome to predict their potential functions. After investigating these 288 SNPs, 157 SNPs returned back with a score indicative of no potential regulatory function. Only 10 SNPs returned with significant scores, indicating the regulatory function and only 3 out of them showed highly significant score. Our results illustrate the future interpretation of GWAS data to include LD structure and different loci association for epilepsy risk.
Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146), 799-816.
Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, 2012. Annotation of functional variation in personal genomes using RegulomeDB. Genome research 22(9), 1790-1797.
Consortium EP. 2012. An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414), 57-74.
Consortium TILAE. 2014. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. The Lancet. Neurology 13(9), 893.
Desmots F, Rauch C, Henry C, Guillouzo A, Morel F. 1998. Genomic organization, 5′-flanking region and chromosomal localization of the human glutathione transferase A4 gene. Biochemical Journal 336(2), 437-442.
Desmots F, Rissel M, Loyer P, Turlin B, Guillouzo A. 2001. Immunohistological analysis of glutathione transferase A4 distribution in several human tissues using a specific polyclonal antibody. Journal of histochemistry & cytochemistry 49(12), 1573-1579.
Doherty C. 2010. Common genetic variation and susceptibility to partial epilepsies: A genome-wide association study.
Fajans SS, Bell GI, Polonsky K. S. 2001. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New England Journal of Medicine 345(13), 971-980.
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, 2014. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4), 475-482.
Guo Y, Baum LW, Sham PC, Wong V, Ng PW, Lui CHT, 2011. Two-stage genome-wide association study identifies variants in CAMSAP1L1 as susceptibility loci for epilepsy in Chinese. Human molecular genetics ddr550.
Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, 2009. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences 106(23), 9362-9367.
Hubatsch I, Ridderström M, Mannervik B. 1998. Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation. Biochemical Journal 330(1), 175-179.
Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, De Bakker PI. 2008. SNAP: a web-based tool for identification and annotation of proxy SNPs using Hap Map. Bioinformatics 24(24), 2938-2939.
Johnson CM, Hill CS, Chawla S, Treisman R, Bading H. 1997. Calcium controls gene expression via three distinct pathways that can function independently of the Ras/mitogen-activated protein kinases (ERKs) signaling cascade. The Journal of neuroscience 17(16), 6189-6202.
Kasperavičiūtė D, Catarino CB, Matarin M, Leu C, Novy J, Tostevin A, 2013. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A. Brain 136(10), 3140-3150.
Kim HJ, Won HH, Park KJ, Hong SH, Ki CS, Cho SS, 2013. SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15). PloS one 8(11), e79063.
Ma J, Chen M, Wang J, Xia HH, Zhu S, Liang Y, 2008. Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer. Carcinogenesis 29(7), 1327-1333.
Rogaev E, Lukiw W, Vaula G, Haines J, Rogaeva E, Tsuda T, 1993. Analysis of the c‐FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer’s disease. Neurology 43(11), 2275-2275.
Sillanpää M, Besag F, Aldenkamp A, Caplan R, Dunn DW, Gobbi G. 2016. Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epidemiology of psychiatric/ behavioural disorder in children with epilepsy. Epileptic Disorders 1(1).
Speed D, Hoggart C, Petrovski S, Tachmazidou I, Coffey A, Jorgensen A, 2014. A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy. Human molecular genetics 23(1), 247-258.
Steffens M, Leu C, Ruppert AK, Zara F, Striano P, Robbiano A, 2012. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16. 1, 2q22. 3 and 17q21. 32. Human molecular genetics 21(24), 5359-5372.
Weiss S, Gottfried I, Mayrose I, Khare SL, Xiang M, Dawson SJ, 2003The DFNA15 deafness mutation affects POU4F3 protein stability, localization, and transcriptional activity. Molecular and cellular biology 23(22), 7957-7964.
Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, 2014. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic acids research 42(D1), D1001-D1006.
Zhang J, Zhang D, McQuade JS, Behbehani M, Tsien JZ, Xu M. 2002. c-fos Regulates neuronal excitability and survival. Nature genetics 30(4), 416-420.
Rubina Dad, Muhammad Ikram Ullah, Amjad Ali, Muhammad Jawad Hassan, 2017. Identification of biological functions of risk loci associated with complex epilepsy: An in-silico approach for data analysis. Int. J. Biosci., 10(3), 388-398.
Copyright © 2017 by the Authors. This article is an open access article and distributed under the terms and conditions of the Creative Commons Attribution 4.0 (CC BY 4.0) license.