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

Abstract

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.