| | Category | CBIO | L11 | Utilizing the WGCNA package in R to Identify Biomarkers for |
| | Infantile Spasms |
| | Abstract | Infantile spasms (IS) is a seizure disorder that affects children in the |
| | first 2 years of life, usually between the ages of 4-8 months. IS has a |
| | very subtle appearance making it difficult to recognize and diagnose. |
| | Approximately 30% of IS cases are idiopathic. In order to improve |
| | current diagnostic methods, my project focuses on identifying |
| | biomarkers for infantile spasms. The DMC Children’s Hospital Lab |
| | collected surgical type brain tissue data from patients with epilepsy, |
| | both those with and without IS. They extracted total RNA from the brain |
| | tissues of both IS (n=17) and other of epilepsies (referred to as "Non- |
| | IS"; n=18) and measured gene expression levels using Agilent |
| | Sureprint microarrays. This gene expression data for 35 samples |
| | containing 32,080 genes collected by DMC Children’s Hospital Lab was |
| | used as an input for my project. Since genes operate in networks, I |
| | began by analyzing the data using the weighted gene co-expression |
| | network analysis (WGCNA) method. The WGCNA package, in the R |
| | programming language, was used to construct and analyze the gene |
| | networks and to detect modules significant for IS. This was followed by |
| | the selection of genes significant for IS and further analysis using the |
| | gene ontology enrichment analysis tool. Gene network visualization was |
| | done by constructing eigengene heatmaps. A total of 73 modules were |
| | detected, out of which 3 modules (#9, #16 and #31) were highly |
| | associated with IS. |
| | |
| | Within each of these 3 modules, the top 15 significant genes were |
| | further investigated using https://toppgene.cchmc.org to research |
| | associated terms. In module #31, 3 genes were found significant for IS: |
| | KLHL17, PLCB1, and KCNT1. Gene KLHL17 is known to play a major |
| | role in actin-based regulation of neuronal function and mutations in this |
| | gene can cause West Syndrome, Epilepsy, and X-linked Infantile |
| | Spasm Syndrome. Gene PLCB1 is expressed in the amygdala, cerebral |
| | cortex, hippocampus, lateral septum, and olfactory bulb and is related |
| | to hypsarrhythmia -- a common symptom of infantile spasms. Malignant |
| | migrating partial seizures of infancy (MMPSI) are caused by mutations |
| | in KCNT1 during early embryonic development. In module #9, one gene |
| | NTNG2 was found significant for IS. NTNG2 controls both neuronal |
| | circuit formation and neurite outgrowth of axons and dendrites. Using |
| | the coregulate-genes analysis website dire.dcode.org, the following |
| | transcription factors were predicted to regulate the co-expression of the |
| | significant genes in three modules: PBX, PIT1, CIZ, TEF, AIRE, E47, |
| | EBOX, PBX1, HMEF2, and XFD2. A preliminary identification of such |
| | key genes and the transcription factors provides a starting point in |
| | design of new therapeutic drugs to manage infantile spasms. However, |
| | additional, detailed in-vitro and in-vivo studies are needed to first |
| | validate these targets. |
| | Bibliography | https://www.ninds.nih.gov/Disorders/All-Disorders/Infantile-Spasms- |
| | Information- |
| | Pagehttps://labs.genetics.ucla.edu/horvath/CoexpressionNetwork/Rpac |
| | kages/WGCNA/ |