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A Complex Trait Genomics Approach to Investigating Amyotrophic Lateral Sclerosis

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A Complex Trait Genomics Approach to Investigating Amyotrophic Lateral Sclerosis A Complex Trait Genomics Approach to Investigating Amyotrophic Lateral Sclerosis Restuadi Bachelor of Science, Master of Bioinformatics (Advanced) https://orcid.org/0000-0001-8434-4465 A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2020 Institute For Molecular Bioscience 2 Abstract Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is a fatal neurodegenerative disease that has a lifetime risk of 1 in 300 people worldwide, with death often occurring within 3 to 5 years from the onset of symptoms. Currently, there is no effective treatment and no cure for ALS, in part due to a limited understanding of its aetiology. Most ALS genetics research to date is driven by discoveries in the familial form of the disease, where causality seems to reflect a heritable single gene mutation. Only a small proportion of ALS research is focussed on investigating the cause of sporadic ALS, which is likely to be a complex genetic disorder with many factors contributing to its aetiology, including genetic and environmental risk factors. The traditional ALS genetic research approaches which only rely on familial data or the single-trait Genome Wide Association Study (GWAS) paradigm might not be ideal for studying complex disorders like ALS. Therefore, the research presented in this thesis aims to study the aetiology of ALS using statistical techniques that have been developed for genetic analysis of complex traits applied to publicly available summary statistics level GWAS and multi-omics data. Newly available gut microbiome data was also used to understand non-genetic factors on the development of disease. Using more than 200 publicly available GWAS summary statistics from various traits to estimate genetic correlations with ALS, I found a negative correlation between ALS with cognitive performance (CP) and with education attainment (EA). This analysis also confirmed the previously reported positive correlation with schizophrenia (SCZ). Adding support for these genetic correlations, I was able to leverage ALS polygenic risk score prediction by multi- traits methods (MTAG and SMTpred) using these correlated traits. Furthermore, cell-type enrichment analyses of these traits showed that many central nervous system tissues relevant to ALS are also found to be highly significant in its correlated traits (CP, EA, SCZ). Genes expressed in dendritic cell were found to be significantly enriched in ALS association results which might suggest immune system involvement in ALS aetiology. The post-GWAS analysis of the largest unpublished ALS European ancestry GWAS (139,452 individuals) using Bayesian methodology suggested that ALS genetic architecture is likely to be less polygenic, has greater relative contribution from rare variants and has greater indication of negative selection compared to other common diseases. Using Summary Based Mendelian Randomisation (SMR) analysis, I provided support that ALS associated SNPs could 3 play a causal role mediated through gene expression in brain and blood (SCFD1, RES18, MOBP, SLC98A, GGNBP2, DHRS11, ZNHIT3, MYO19, G2E2, SARM1). Moreover, most of these causal gene annotations are linked to protein processing in endoplasmic reticulum and cytoskeletal function that is relevant to previously reported ALS aetiology. By comparing SMR result with the correlated traits, I also found that CP has causal gene overlap with ALS. Moreover, the SMR significant genes for CP have an inflated SMR P-value distribution which could suggest functional overlap in both traits. The gut microbiome study of MND (where the majority of cases are ALS), suggests that there is no significant difference in term of composition or richness between ALS and healthy controls. The result showed that 4 ALS patients had dysbiosis, but with our current sample size, the possibility that this dysbiosis is a chance result cannot be excluded. By analysing the ALS patient survival status with the microbiome richness index (Shannon index), ALS patients with higher microbiome richness were found to have faster progression and mortality. This finding challenges the common notion that higher microbiome richness leads to better health. Despite all of these findings, it is still not clear whether the gut microbiome composition contributes to the cause of ALS or is just a consequence of ALS. 4 Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution of others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, study design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. 5 Publications included in this thesis 1. Restuadi Restuadi, Fleur C. Garton, Beben Benyamin, Tian Lin, Kelly L Williams, Anna Vinkhuyzen, Wouter van Rheenen, Zhihong Zhu, Nigel G. Laing, Karen A. Mather, Perminder S. Sachdev, Shyuan T Ngo, Frederik J. Steyn, Leanne Wallace, Anjali K Henders, Peter M Visscher, Merrilee Needham, Susan Mathers, Garth Nicholson, Dominic B. Rowe, Robert D. Henderson, Pamela A. McCombe, Roger Pamphlett, Ian P Blair, Naomi R Wray, Allan F McRae : Polygenic Risk Score Analysis for Amyotrophic Lateral Sclerosis Leveraging Cognitive Performance, Educational Attainment and Schizophrenia European Journal of Human Genetics (Accepted for Publication) 2020 This publication has been incorporated as Chapter 2. Contributor Statement of contribution Restuadi Restuadi (Candidate) Analysis and interpretation (80%) Drafting and production (70%) Naomi R Wray Conception and design Allan F McRae Analysis and interpretation (10% total) Drafting and production (15%) Leanne Wallace Genotype data generation Anjali K Henders Fleur C. Garton Analysis and interpretation (10% total) Beben Benyamin Tian Lin Zhihong Zhu Peter M Visscher Anna Vinkhuyzen Wouter van Rheenen Kelly L Williams These authors provided biological samples Nigel G. Laing Karen A. Mather Perminder S. Sachdev Shyuan T Ngo Frederik J. Steyn Merrilee Needham Susan Mathers Garth Nicholson Dominic B. Rowe Robert D. Henderson Pamela A. McCombe Roger Pamphlett Ian P Blair 6 2. Pamela A McCombe, Robert D Henderson, Aven Lee, John D Lee, Trent M Woodruff, Restuadi Restuadi, Allan F McRae, Naomi R Wray, Shyuan Ngo, Frederik J Steyn: Gut microbiota in ALS: possible role in pathogenesis? Expert review of neurotherapeutics, 1-21: 2019 This publication is a review article about the possible pathogenesis of ALS that involves the gut microbiome. I and my supervisors (Naomi R Wray and Allan F McRae) contributed the whole of chapter 2 of the paper (Gut microbiome methodology reviews) that makes up ~20% of the published review and describes methodology for analysis of microbiome data. I incorporated this methodology review into Chapter 4 (Gut microbiome chapter, specifically sections 4.1.1 and 4.1.2) in this thesis. Contributor Statement of contribution Restuadi Restuadi (Candidate) Literature review (80%) Drafting and production (60%) Naomi R Wray Literature review (20% total) Allan F McRae Drafting and production (30%) Frederik J Steyn Drafting and production (10% total) 7 3. Shyuan T Ngo*, Restuadi Restuadi*, Allan F McRae, Ruben P Van Eijk, Fleur Garton, Robert D Henderson, Naomi R Wray, Pamela A McCombe, Frederik J Steyn: Progression and survival of patients with motor neuron disease relative to their faecal microbiota, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, DOI: 10.1080/21678421.2020.1772825 : 2020 In this publication, I shared the first authorship (*) with Dr. Shyuan Ngo. I conducted the analyses and interpretation of the gut microbiome and this publication has been incorporated as Chapter 4 (specifically section 4.2 to 4.5). Contributor Statement of contribution Restuadi Restuadi* (Candidate) Analysis and interpretation (60%) Drafting and production (40%) Shyuan T Ngo* Analysis and interpretation (20%) Drafting and production (40%) Conception and design (40%) Sample recruitment and processing (30%) Providing clinical data/record (30%) Frederik J Steyn Analysis and interpretation (10%) Drafting and production (10%) Conception and design (50%) Sample
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