Study participants and ethics approval from case control cohorts

A combined cohort of 471 Caucasian North American sALS patients and 496 Caucasian North American healthy age-matched controls were used in this study. Participants were diagnosed by board-certified neurologists and met the revised El Escorial World Federation of Neurology criteria for diagnosis of ALS³². Routine screening for known ALS genetic mutations was not undertaken. Retrospective genotyping of DNA samples was approved by the Human Research Ethics committee of the University of Western Australia (RA/4/20/5308). DNA and clinical information including age of onset, site of disease onset and survival duration, were collected from 138 sALS patients at Duke ALS clinics in accordance with the Health Insurance Portability and Accountability Act (Pro00040665/323682). In addition, DNA samples from 333 sALS patients and 496 population control samples were obtained from the NINDS Repository, Coriell Institute for Medical Research (New Jersey, USA).