Abstract
The ability to finely control our movement is key to achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown. Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature. Here we present the first genome-wide association study to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children, providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N = 4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance, however, 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNPs, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20, and ADAM21. Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.
Highlights
4https://www.internationalgenome.org/data-portal/data-collection/hgdp 5https://zzz.bwh.harvard.edu/gpc met genome-wide association (P ≤ 5 × 10−8), we identified 59 single nucleotide polymorphisms (SNPs) across seven genomic regions that met the threshold for suggestive significance at P ≤ 1 × 10−5 (Figure 3)
None of the top 59 SNPs from the motor coordination genome-wide association study (GWAS) were found to be associated with motor difficulty case-control status (Bonferroni correct P threshold is set to 8.5 × 10−4 to account for multiple testing)
While no SNPs reached the threshold for genome-wide significance (P ≤ 5 × 10−8), three chromosome regions (3p25.2, 6p12.1, and 14q24.2) contained more than one suggestively associated SNP (P ≤ 1 × 10−5)
Summary
Developmental coordination disorder (DCD) is a neurodevelopmental condition defined by the DSM-5 as a severe impairment of motor skills, usually presenting in early childhood, and in the absence of any other explanatory factor such as a known neurological disorder (e.g., cerebral palsy, acquired brain injury, visual impairment, or intellectual disability) (American Psychiatric Association, 2013). In cases where individuals carried a pathogenic CNV known to cause other neurodevelopmental disorders (e.g., the 16p11.2 deletion which results in CAS), Cunningham et al (2019) showed that carriers of these pathogenic CNVs were more likely to have coordination difficulties While this does not demonstrate a clear association between specific CNVs and coordination, it suggests a link between known causes of neurodevelopmental disorders and motor function. The ALSPAC cohort provides data on a subset of children across four of the individual MABC tasks: heel-to-toe walking, placing pegs, threading lace and throwing a bean bag into a box (Henderson and Sugden, 1992) These test items represent the most robust measure of fine and gross coordination in children with associated genetic data. We report the first genes to be directly implicated in motor coordination in children, generating the first window into the genetic basis of DCD
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