{ "abstract": "Background Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case–control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.Methods We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.Results In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.Conclusions Our findings represent the first large-scale, case–control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.", "authors": [ { "affiliations": [ "Department of Biostatistics and Health Informatics, King's College London, London, UK", "Department of Basic and Clinical Neuroscience, King's College London, London, UK", "Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia", "Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK" ], "name": "Alfredo Iacoangeli" }, { "affiliations": [ "Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada", "Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada" ], "name": "Allison A Dilliott" }, { "affiliations": [ "Department of Basic and Clinical Neuroscience, King's College London, London, UK" ], "name": "Ahmad Al Khleifat" }, { "affiliations": [ "Clinical Science, Neurosciences, Umeå Universitet Medicinska Fakulteten, Umea, Sweden" ], "name": "Peter M Andersen" }, { "affiliations": [ "Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, Koç University School of Medicine, Istanbul, Turkey" ], "name": "Nazlı A Başak" }, { "affiliations": [ "Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK" ], "name": "Johnathan Cooper-Knock" }, { "affiliations": [ "UMR 1253, Université de Tours, Inserm, Tours, France", "Centre de référence sur la SLA, CHU de Tours, Tours, France" ], "name": "Philippe Corcia" }, { "affiliations": [ "Centre de référence sur la SLA, CHRU de Limoges, Limoges, France", "UMR 1094, Université de Limoges, Inserm, Limoges, France" ], "name": "Philippe Couratier" }, { "affiliations": [ "Instituto de Fisiologia, Universidade de Lisboa, Lisbon, Portugal" ], "name": "Mamede deCarvalho" }, { "affiliations": [ "Department of Neurology, Sourasky Medical Centre, TelAviv, Israel", "Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel" ], "name": "Vivian E Drory" }, { "affiliations": [ "Neurology, Emory University, Atlanta, Georgia, USA" ], "name": "Jonathan D Glass" }, { "affiliations": [ "Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel", "Department of Neurology, Hadassah Medical Center, Jerusalem, Israel" ], "name": "Marc Gotkine" }, { "affiliations": [ "Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel", "Department of Neurology, Hadassah Medical Center, Jerusalem, Israel" ], "name": "Yosef M Lerner" }, { "affiliations": [ "Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland" ], "name": "Orla Hardiman" }, { "affiliations": [ "Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA" ], "name": "John E Landers" }, { "affiliations": [ "Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland" ], "name": "Russell L McLaughlin" }, { "affiliations": [ "ALS Unit, San Rafael Hospital, Madrid, Spain" ], "name": "Jesus S Mora Pardina" }, { "affiliations": [ "School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, Belfast, UK" ], "name": "Karen Morrison" }, { "affiliations": [ "Instituto de Fisiologia, Universidade de Lisboa, Lisbon, Portugal" ], "name": "Susana Pinto" }, { "affiliations": [ "Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain" ], "name": "Monica Povedano" }, { "affiliations": [ "Department of Basic and Clinical Neuroscience, King's College London, London, UK" ], "name": "Christopher E Shaw" }, { "affiliations": [ "Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK" ], "name": "Pamela J Shaw" }, { "affiliations": [ "Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy", "Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy" ], "name": "Vincenzo Silani" }, { "affiliations": [ "Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy", "Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy" ], "name": "Nicola Ticozzi" }, { "affiliations": [ "Department of Neuroscience, Leuven Brain Institute (LBI), VIB, Center for Brain and Disease Research, University of Leuven, Leuven, Belgium", "Department of Neurology, University Hospitals Leuven, Leuven, Belgium" ], "name": "Philip van Damme" }, { "affiliations": [ "Department of Neurology, University Medical Centre Utrecht Brain Centre, Utrecht, Netherlands" ], "name": "Leonard H van den Berg" }, { "affiliations": [ "UMR 1253, Université de Tours, Inserm, Tours, France", "Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France" ], "name": "Patrick Vourc'h" }, { "affiliations": [ "Neuromuscular Diseases Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland" ], "name": "Markus Weber" }, { "affiliations": [ "Department of Neurology, University Medical Centre Utrecht Brain Centre, Utrecht, Netherlands" ], "name": "Jan Herman Veldink" }, { "affiliations": [ "Department of Biostatistics and Health Informatics, King's College London, London, UK", "Department of Basic and Clinical Neuroscience, King's College London, London, UK", "Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia", "Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK", "Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada", "Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada", "Clinical Science, Neurosciences, Umeå Universitet Medicinska Fakulteten, Umea, Sweden", "Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, Koç University School of Medicine, Istanbul, Turkey", "Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK", "UMR 1253, Université de Tours, Inserm, Tours, France", "Centre de référence sur la SLA, CHU de Tours, Tours, France", "Centre de référence sur la SLA, CHRU de Limoges, Limoges, France", "UMR 1094, Université de Limoges, Inserm, Limoges, France", "Instituto de Fisiologia, Universidade de Lisboa, Lisbon, Portugal", "Department of Neurology, Sourasky Medical Centre, TelAviv, Israel", "Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel", "Neurology, Emory University, Atlanta, Georgia, USA", "Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel", "Department of Neurology, Hadassah Medical Center, Jerusalem, Israel", "Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland", "Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA", "Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland", "ALS Unit, San Rafael Hospital, Madrid, Spain", "School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, Belfast, UK", "Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain", "Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy", "Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy", "Department of Neuroscience, Leuven Brain Institute (LBI), VIB, Center for Brain and Disease Research, University of Leuven, Leuven, Belgium", "Department of Neurology, University Hospitals Leuven, Leuven, Belgium", "Department of Neurology, University Medical Centre Utrecht Brain Centre, Utrecht, Netherlands", "Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France", "Neuromuscular Diseases Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland", "Department of Genetics, McGill University, Montreal, Quebec, Canada", "Department of Neurology, King’s College Hospital, London, UK" ], "name": "Project MinE ALS Sequencing Consortium" }, { "affiliations": [ "Department of Biostatistics and Health Informatics, King's College London, London, UK", "Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK" ], "name": "Richard Dobson" }, { "affiliations": [ "Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada", "Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada", "Department of Genetics, McGill University, Montreal, Quebec, Canada" ], "name": "Guy A Rouleau" }, { "affiliations": [ "Department of Basic and Clinical Neuroscience, King's College London, London, UK", "Department of Neurology, King’s College Hospital, London, UK" ], "name": "Ammar Al-Chalabi" }, { "affiliations": [ "Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada", "Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada", "Department of Genetics, McGill University, Montreal, Quebec, Canada" ], "name": "Sali M K Farhan" } ], "title": "Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications", "uid": "9e77f5a6-d4d0-5668-bd92-ee5711bd4525" }