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Investigating the Molecular Basis of Concussion Using INVESTIGATING THE MOLECULAR BASIS OF CONCUSSION USING WHOLE EXOME SEQUENCING AND BIOINFORMATICS Omar Ezzeldin Ibrahim Abdelrahman BBehavSc(HonsPsych), GCertBiotech Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Biomedical Sciences Faculty of Health Queensland University of Technology 2021 LIST OF PUBLICATIONS: 1- Heidi G. Sutherland, Neven Maksemous, Cassie L. Albury, Omar Ibrahim, Robert A. Smith, Rod A. Lea, Larisa M. Haupt, Bronwyn Jenkins, Benjamin Tsang, Lyn R. Griffiths. Comprehensive exonic sequencing of hemiplegic migraine related genes in a cohort of suspected probands identifies known and potential pathogenic variants. Accepted in Cells. 2- Ibrahim O, Sutherland HG, Maksemous N, Smith R, Haupt LM, Griffiths LR. Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach. J Neurotrauma. 2020 Sep 1;37(17):1870-1879. doi: 10.1089/neu.2019.6962. Epub 2020 May 4. PMID: 32233732; PMCID: PMC7462038. Q1 Journal 3- Maksemous N, Smith RA, Sutherland HG, Maher BH, Ibrahim O, Nicholson GA, Carpenter EP, Lea RA, Cader MZ, Griffiths LR. Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine. Cephalalgia Reports. 2019 Oct 11;2:2515816319881630. 4- Ibrahim O, Sutherland HG, Haupt LM, Griffiths LR. Saliva as a comparable-quality source of DNA for Whole Exome Sequencing on Ion platforms. Genomics. 2020 Mar;112(2):1437-1443. doi: 10.1016/j.ygeno.2019.08.014. Epub 2019 Aug 21. PMID: 31445087. Q1 Journal 5- Ibrahim O, Sutherland HG, Avgan N, Spriggens LK, Lea RA, Haupt LM, Shum DH, Griffiths LR. Investigation of the CADM2 polymorphism rs17518584 in memory and executive functions measures in a cohort of young healthy individuals. Neurobiology of learning and memory. 2018 Nov 1;155:330-6. Q1 Journal. CONCUSSION GENETICS i 6- Ibrahim O, Sutherland HG, Haupt LM, Griffiths LR. An emerging role for epigenetic factors in relation to executive function. Briefings in functional genomics. 2017 Nov 20;17(3):170- 80. Q1 Journal. 7- Avgan N, Sutherland HG, Spriggens LK, Yu C, Ibrahim O, Bellis C, Haupt LM, Shum DH, Griffiths LR. BDNF variants may modulate long-term visual memory performance in a healthy cohort. International journal of molecular sciences. 2017 Mar 17;18(3):655. Q1 Journal Planned/Under Review 1- Rare Variants and Persistent Post-Concussion Symptoms: an exploratory study. Planned Submission: Frontiers in Molecular Neuroscience – Q1 2- Mitochondrial Variants and Post-Concussion Migraine: A whole exome approach. Planned submission: International Journal of Molecular Sciences. – Q1 3- A Machine Learning approach to investigating concussion and head trauma outcomes. Under Review: Journal of Molecular Medicine – Q1 LIST OF CONFERENCES: Oral Presentations: 1- O.Ibrahim, H. Sutherland, R. Lea, L. Haupt, L. Griffiths. : A novel approach to identify functional genetic variants associated with persistent post-concussion symptoms. Oral Presentation. Australasian Neuroscience Society, Adelaide, December 2019. 2- O. Ibrahim, H.Sutherland, L. Haupt, L. Griffiths. Investigating the molecular basis of concussion susceptibility. IHBI Inspires. Oral Presentation. Brisbane, August 2018. ii CONCUSSION GENETICS Poster Presentations: 1. O. Ibrahim, H.Sutherland, P. Dunn, L. Haupt, L. Griffiths. , An alternative approach to investigating neurological disturbances following head trauma, Gene Mappers, Sydney, November 2019. 2. O. Ibrahim, H.Sutherland, L. Haupt, L. Griffiths. Genetics of Post-Concussion Symptoms.ASMR Post Graduate Conference. Brisbane, May 2019. 3. O. Ibrahim, H.Sutherland, L. Haupt, L. Griffiths. Exploring Mutations Implicated in Severe Reactions to Trivial Head Trauma. Human Genetics Society of Australasia Annual Scientific Meeting, Sydney, August 2018. 4. H. Sutherland, N. Maksemous, C. Albury, O. Ibrahim, R. Smith, L. Haupt, R. Lea, and L. Griffiths. PRRT2 mutations in familial hemiplegic migraine. GeneMappers, QLD, 2018. 5. O. Ibrahim, H.G. Sutherland, T. Sheppard, N. Avgan, L.G. Spriggens, L.M. Haupt, D.K. Shum, L.R. Griffiths. Potential role for CADM2 SNP in Visual Memory, Prospective Memory, and Executive Function in Healthy Individuals. Human Genetics Society of Australasia Annual Scientific Meeting, Brisbane, August 2017. 6. Omar Ibrahim, Cassie Albury, Heidi Sutherland, Miles Benton, Larisa Haupt, Lyn Griffiths. Comparing Whole Exome Sequencing Data Quality between Saliva and Blood Samples. ASMR postgraduate conference Queensland, June 2017. CONCUSSION GENETICS iii 7. O. Ibrahim, H.G. Sutherland, N. Avgan, L. M. Haupt, T. Sheppard, L.K. Spriggens, D.H.K. Shum, L.R. Griffiths. HEY1 gene related SNP playing a role in working memory, visual spatial capacity, and verbal recall. ASMR postgraduate conference Queensland, June 2016. Awards and Scholarships: 1- 2019 : European Molecular Biology Laboratory PhD Course Delegate 2- 2018 : Chronic Disease and Ageing Manuscript Award 3- 2018 : QUT Faculty of Health Scholarship 4- 2017 : QUT Bluebox Innovation Camp 1st place, Best Pitch 5- 2017 : QUT PhD Tuition Fee Waiver Scholarship iv CONCUSSION GENETICS Keywords Concussion, mTBI, Neurogenetics, brain injury, next generation sequencing, Whole Exome Sequencing, Post-concussion symptoms, head trauma, head injuries, Machine Learning, Mitochondrial DNA, Epigenetics, Neuronal Vulnerability CONCUSSION GENETICS v Abstract Concussion or mild traumatic brain injury (mTBI) is a transient neurological dysfunction that follows closed head injury. It is often attributed to the acceleration and deceleration forces that cause shear and tear to the neuronal axons. The molecular aftermath of concussion has recently been further understood and has highlighted an important role for neuronal ion channels and neurotransmitters in restoring neuronal homeostasis. These processes are crucial as concussion is often paired with neuronal depolarisation which is suggested to cause most post-concussion symptoms (PCS). Rare variants in ion channel genes (e.g. CACNA1A and ATP1A2) have been implicated in response to head trauma and the ensuing prolonged symptoms, yet most existing research has focussed on single common variant association studies. To date, there is little consensus on the genetic basis of concussion development and outcomes. Further, there are no studies that have explored the use of whole exome sequencing (WES) as well as machine learning (ML) methods to investigate the potential genetic basis of PCS. This PhD project utilised 3 groups of participants: a) N = 16 individuals with severe neurological reactions to trivial head trauma b) N = 26 individuals with persistent post- concussion symptoms; and c) N = 18 individuals who recovered from mTBI within a normal and reasonable time frame (up to 6 weeks). DNA extracted from saliva and whole blood from the same individuals was compared to determine the suitability of saliva as a relevant source of DNA for these groups. WES was undertaken on the Ion Platform Instrumentation (Ion Proton and GeneStudio S5 Plus) with Variant Call Files (VCFs) of groups a and b analysed for rare vi CONCUSSION GENETICS deleterious variants (MAF < 0.01). Mitochondrial variants were also explored in the entire cohort by realigning the WES sequencing data to the mitochondrial reference genome. Finally, methylation changes in sites implicated in previous studies were explored using pyrosequencing methods. Further the VCFs of groups a, b, and c were used to develop an ML model of classification based on genetic variants. Saliva was noted to be a comparable high-quality source of DNA for use in WES interchangeably with whole-blood isolated DNA. This study identified variants in a number of ion channel and neurotransmitter pathways to have a potential role in concussion related symptoms. Using WES, 11 variants were identified in genes implicated in neurological recessive disorders. Rare and novel mutations in Ion Channel genes were found in 5 cases, Neurotransmitter pathway mutations were found in 2 cases, and Ubiquitin related mutations were identified in 4 cases, 2 of whom are related. All the identified mutations were predicted to be deleterious by in-silico and previous studies where possible. WES further identified 42 variants in individuals with persistent PCS. These variants were mostly identified as deleterious by in-silico prediction tools but were predicted to be Variants of Unknown Significance (VUS) in the clinical database Clinvar. These 42 variants were identified to be in genetic pathways similar to the ones identified in the first group with severe neurological symptoms (a). 3 likely pathogenic mitochondrial variants, with one implicated in ATPase pathways, were identified in the larger cohort at a higher frequency similar to publicly available neurological databases and higher than healthy control databases containing similarly sequenced samples. ML models, in particular Gradient Boosted Trees and Random forests were then used and able to classify individuals who recover normally after mTBI and distinguish these from individuals with HM- like symptoms following trivial head trauma and those with persistence PCS with an AUC of 0.7, showing potential future uses in larger cohorts. The application of ML methods also implicated a tau-related gene (TTBK2) and an insulin-resistance related one in post-head trauma CONCUSSION GENETICS vii outcomes. These preliminary results suggest a potential role for combining genomics and AI to tailor treatments and care for mTBI patients, in line with the larger
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