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Genetics and Genomics 31st International Symposium on ALS/MND Theme 02 – Genetics and Genomics GEN-01: An Interval Look at Early outcomes of strength (ATLIS), bulbar function (quantitative speech analysis and IOPI), and disease Markers of Disease in Familial ALS progression (change in ALSFRS-R total score over time). Isabel Anez-Brunzual1, Austin Lewis, Katherine Burke1, Multiple measures of strength (ATLIS, HHD) and Diane Lucente1, Jennifer Jockel-Balsarotti2, Margaret cognition (NIH examiner, ALS-CBS) will be evaluated in all participants over time. Clapp2, Amber Malcolm2, Taylor Stirrat1, Stephanie Berry1, Tania Gendron3, Mercedes Prudencio3, Kathryn Results to date: Connaghan4, James Chan5, Jordan Green4, Leonard Petrucelli3, James Berry1, Timothy Miller2, Dr Katharine Interval analysis will be shown for 86 participants Nicholson1 enrolled in the DIALS Network. Forty-one of 86 1Massachusetts General Hospital, Boston, United States, participants are positive for an ALS causative mutation 2Washington University, Saint Louis, United States, 3Mayo (33 C9orf72, 5 SOD1, 1 TARDBP, 1 VAPB, and 1 FIG4). Clinic, Jacksonville, United States, 4MGH Institute of Health Peri-conversion data will be shown for the 4 C9orf72 Professions, Boston, United States, 5Biostatistics Center, MGH, carriers (3 ALS, 1 FTD) who have developed symptoms. Boston, United States Longitudinal strength, bulbar, and cognitive outcome data as well as direct biomarker comparison will be Live Poster Session A, December 9, 2020, 5:10 PM - 5:50 shown. DIALS enrollment and follow-up visits are PM ongoing. Background: Discussion: The validation of sensitive biofluid markers of inciting The DIALS Network dataset is composed of a growing disease pathology and clinical outcomes is crucial to number of pre-symptomatic ALS gene carriers, now detecting early disease, and to understanding the onset including several symptom converters. Increased of familial ALS and preparing for successful prevention sample size and longitudinal evaluation will continue to trials in asymptomatic gene carriers. inform key elements of the conversion period critical to the design of prevention trials in familial ALS. Objective: To identify the earliest biological markers of disease in Acknowledgements: pre-symptomatic ALS gene carriers Muscular Dystrophy Association, ALS Association, ALS Finding a Cure, Target ALS and philanthropy. Methods: Participants are enrolled in the Dominant Inherited ALS (DIALS) Network at Massachusetts General Hospital and Washington University. Genetic testing of over 30 ALS causative genes and potential genetic modifiers is performed, and participants return every 6 months for clinical outcomes and biofluid collection (plasma, serum, whole blood, CSF, PBMCs, urine, skin biopsy). Clinical data is collected using NeuroBANK. Interval biofluid marker analysis includes longitudinal assessment of neurofilament light chain, chitinases, and dipeptide repeat proteins in collaboration with the Petrucelli and Gendron Labs at the Mayo Clinic in Jacksonville FL and the Bowser lab at the Barrow Neurological Institute. In symptom converters, these candidate biomarkers are directly compared to clinical 1 31st International Symposium on ALS/MND Theme 02 – Genetics and Genomics GEN-02: Blood Transcriptomics of ALS 2MIU IL-2. They underwent infusions once daily for 5 days every 28 days for a total of 3 months. Blood Patients in the IMODALS Clinical Trial samples were collected at different time points Ms Ilaria Giovannelli1, Mr Marius Mickunas2, Dr Timothy throughout the trial. White blood cells were isolated Tree2, Prof Gilbert Bensimon3, Prof Nigel Leigh5, Dr Paul and RNA extracted. This was then used to generate microarray gene expression data and for validation Heath1, Prof Dame Pamela Shaw1, Prof Janine Kirby1 1Sheffield Institute for Translational Neuroscience, Department through nanoString and qRT-PCR. of Neuroscience, University of Sheffield, Sheffield, United Kingdom, 2Department of Immunobiology, Faculty of Life Findings: Science and Medicine, King's College London, London, United Blood transcriptome of these patients was analysed at Kingdom, 3Department of Biostatistics, Clinical Epidemiology, day 8 (after the first treatment cycle), 64 (after the third Public Health and Innovation in Methodology (BESPIM), Nîmes and last cycle) and 85 (during follow-up) and changes University Hospital, Nimes, France, 4Department of over the treatment course and under different Pharmacology, AP-HO Sorbonne University, Pitié-Salpêtrière administration regimens were evaluated. Gene 5 Hospital, Paris, France, The Trafford Centre for Biomedical expression analysis together with pathway analysis Research, Brighton and Sussex Medical School, Falmer, revealed a prompt immune-regulatory effect of ld-IL-2 Brighton , United Kigdom after the first treatment cycle with evidence of Live Poster Session A, December 9, 2020, 5:10 PM - 5:50 downregulation of pro-inflammatory processes. This PM early response seemed to diminish during the course of the trial but a robust activation of Treg was only visible Background: after the last treatment cycle. In fact, a time-dependent A spreading inflammatory condition within the CNS, and dose-dependent induction of Treg markers was involving both resident and peripheral immune cells, is registered at day 64 suggesting a cumulative effect of characteristic of amyotrophic lateral sclerosis (ALS). ld-IL-2 on these cells. However, inter-individual Regulatory T cells (Treg) are immune regulators which dissimilarities were identified and patients were suppress the establishment of excessive inflammatory classified into low, mild and high responders. Significant conditions and autoimmune disorders. These cells are transcriptional differences were reported amongst dramatically and progressively reduced in ALS patients these groups in their baseline expression of an and this correlates with the rate of disease progression. immunological transcript cluster. In particular, a more Moreover, evidence shows their functional impairment inflammatory-prone phenotype was documented in ALS individuals. Low-dose interleukin-2 (ld-IL-2) has amongst low responders at recruitment. Finally, a been proposed as a therapeutic strategy to promote predictive biomarker analysis was then carried out to Treg expansion and a physiological restoration of the identify small sets of transcripts able to forecast an ALS immune balance. This cytokine is crucial for Treg individual's reaction to ld-IL-2. We discovered that the differentiation, activation and functions and thus it is expression of two genes was able to predict Treg count hypothesized to boost Treg-mediated immune- at the end of the trial, given their gene expression at suppression and dampen neuroinflammation in these time of recruitment. patients. Aim: To evaluate the effect of ld-IL-2 on the blood transcriptome of ALS patients included in the IMODALS clinical trial (NCT02059759). Methods: Thirty-six ALS patients were recruited and randomly assigned to three treatment arms: placebo, 1MIU or 2 31st International Symposium on ALS/MND Theme 02 – Genetics and Genomics GEN-03: Dissecting the sex-dependent significantly enriched in genes highly expressed in the brain, consistent with the known aetiology of ALS. genetic architecture of amyotrophic Finally, per-chromosome heritability estimates (GREML) lateral sclerosis showed a linear relationship with chromosome length in females (r2=0.27;p=0.0074), but not males Mr Ross Byrne1, Dr Wouter van Rheenen2, Prof Jan (r2=0.009,p=0.286) suggesting ALS is more polygenic in Veldink2, Dr Russell L McLaughlin1 females. This observation was supported by analysis 1Smurfit Institute of Genetics ,Trinity College Dublin, Dublin, using Heritability Estimation from Summary Statistics 2 Ireland, Department of Neurology and Neurosurgery, (HESS), which showed a greater proportion of the University Medical Center Utrecht, Utrecht, The Netherlands genome contributed to ALS heritability in females. Our Live Poster Session A, December 9, 2020, 5:10 PM - 5:50 findings suggest the genetic component of ALS differs PM between sexes. Sex affects the prevalance[1], site of onset[1], and even References: heritability[2] of ALS, with evidence that both male[3] 1. McCombe PA, Henderson RD. Gend Med. and female[4,5] sex hormones modify disease risk. 2010;7: 557–570. However, to date the extent to which sex affects the 2. Ryan M et al. JAMA Neurol. 2019. genetic architecture of ALS has not been addressed. doi:10.1001/jamaneurol.2019.2044 We calculated the genetic overlap between sexes in ALS 3. Leigh PN et al. J Neurol Neurosurg Psychiatry pedigrees using published sex-stratified heritability 2011;82(6):635-7 estimates[2], showing an imperfect genetic correlation 4. de Jong S et al. J Neurol. 2013;260: 507–512. between males and females of just 62.8% (48%-73.2%). 5. Rooney JPK et al. Neurology. 2017;89: 1283– To answer whether this can be explained by common 1290. variants, we reanalysed 36,052 samples from a 6. van Rheenen W et al. Nat Genet. 2016;48: published ALS GWAS[6], accounting for gene-by-sex 1043–1048 interactions. Firstly, we ran GREML analysis of ALS heritability fitting sex as an interaction term and observed significant evidence of a gene-by-sex interaction (likelihood-ratio test: p=0.0087) accounting for 1/3rd of the total SNP heritability. Next we ran GWAS using linear mixed model on stratified male- specific (N=18,732) and female-specific (N=17,322) subsets of the data to further dissect sex effects. We estimated heritability using
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