Sex-specific risk loci and modified MEF2C expression in ALS

Significantly more men develop amyotrophic lateral sclerosis (ALS) than women, and heritability is not uniform between male and female transmissions, together suggesting a role for sex in the genetic aetiology of the disease. We therefore performed sex-stratified genome-wide and transcriptome-wide analyses of ALS risk, identifying six novel sex-specific risk loci including MEF2C , which shows increased expression in female ALS motor neurones. X-chromosome analysis revealed an additional risk locus at IL1RAPL2 . ### Competing Interest Statement J.H.V. reports to have sponsored research agreements with Biogen and AstraZeneca. AAK is a consultant for NESTA. AAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals. All other authors have nothing to declare. ### Funding Statement This study was funded by the MND Association of England, Wales and Northern Ireland under grant number 879-791. This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) under Grant Number 21/RC/10294 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners. R.P.B. currently receives support from the MND Association (979-799). A.I. is funded by South London and Maudsley NHS Foundation Trust, MND Scotland, Motor Neurone Disease Association, National Institute for Health and Care Research, Spastic Paraplegia Foundation, Rosetrees Trust, Darby Rimmer MND Foundation, the Medical Research Council (UKRI), Alzheimer's Research UK and LifeArc. This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association, My Name'5 Doddie Foundation, and Alan Davidson Foundation. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Please see attached .tsv file detailing IRB approval as requested I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The GWAS summary statistics generated in this study will be made publicly available upon publication in the NHGRI-EBI GWAS Catalog at https://www.ebi.ac.uk/gwas/ (for female, male and X chromosome meta-analyses, respectively) and through the Project MinE website (https://www.projectmine.com/research/download-data/).