Genome-wide association meta-analysis of age at onset of walking

Onset of walking is a developmental milestone with wide individual differences and high heritability in humans. In this genome-wide association study meta-analysis of age at onset of walking (N=70,560 European-ancestry infants), SNP-based heritability was 24.13% (SE=1.16%) with ∼11.9K variants accounting for about 90% of it, suggesting high polygenicity. We identified 11 independent genome-wide significant loci, including a “double hit” haplotype in which both decreased expression of RBL2 and a potentially deleterious missense variant in RBL2 are associated with delayed walking. Age at onset of walking (in months) was negatively genetically correlated with ADHD and BMI, and positively genetically correlated with intelligence, educational attainment, and adult brain gyrification. The polygenic score showed out-of-sample prediction of 3-5.6%, confirmed to be largely due to direct effects in sib-pair analyses, and was associated with volume of neonatal brain structures involved in motor control. This offers new biological insights of clinical relevance into neurodevelopment. ### Competing Interest Statement Ole A. Andreassen is a consultant to cortechs.ai, speakers honoraria from Janssen, Lundbeck, Sunovion. Stephan J. Sanders receives research funding from BioMarin Pharmaceutical. ### Funding Statement Simons Foundation. Economic and Social Research Council. South-Eastern Norway Regional Health Authority. Research Council of Norway (RCN). UK Medical Research Council. Medical Research Council Centre for Neurodevelopmental Disorders, Kings College London. European Research Council. National Institute for Health Research (NIHR). KG Jebsen Stiftelsen. National Institute of Mental Health. Health Data Research UK. Research Council of Norway. Stiftelsen Kristian Gerhard Jebsen. Trond Mohn Foundation. The Novo Nordisk Foundation. The University of Bergen. The Western Norway Regional Health Authority. The Dutch Ministry of Health, Welfare and Sport. The Dutch Ministry of Economic Affairs. The University Medical Center Groningen (UMCG). The Groningen University. The Provinces in the North of the Netherlands (Drenthe, Friesland, Groningen). Netherlands Organization for Scientific research. The Biobanking and Biomolecular Resources Research Infrastructure. Amsterdam Public Health (APH). Neuroscience Campus Amsterdam (NCA). European Community 7th Framework Program. The Rutgers University Cell and DNA Repository cooperative agreement. The National Institute of Health (NIH). The Rutgers University Cell and DNA Repository cooperative agreement. The Collaborative Study of the Genetics of DZ twinning. The Developmental Study of Attention Problems in Young Twins. Major depression: stage 1 genome-wide association in population-based samples. Determinants of Adolescent Exercise Behavior. Grand Opportunity grants Integration of Genomics and Transcriptomics. Developmental Trajectories of Psychopathology. The Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). ### 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: The Departmental Ethics Committee of the Psychological Science Department of Birkbeck, University of London gave ethical approval for this work. 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 All data produced in the present study are available upon reasonable request to the authors