Genome-Wide Association Study of Motor Coordination

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.

Keywords: ALSPAC; GWAS; coordination; development; developmental coordination disorder; dyspraxia; motor coordination; neurodevelopment.

FIGURE 1

Distribution of MABC test items age adjusted. (A) Heel-to-toe walking (F7CR015) showing the number of steps taken (high score denotes good performance). (B) Placing pegs (F7CR105) showing the time taken to complete the task (low score denotes good performance). (C) Threading lace task (F7CR211) showing the time taken to complete the task (low score denotes good performance). (D) Throwing bean bag (F7CR331) showing the number of throws that successfully hit the target (high score denotes good performance).

FIGURE 2

Distribution of summed motor coordination measures (SumQMS4) derived from the MABC test components to reflect an overall motor coordination score, and a maximum possible score of 40.

FIGURE 3

(A) Genome-wide association shown by a Manhattan plot indicating regions of nominal significance. Each point refers to a single genetic variation (SNP). The X-axis shows the position of SNPs along each of the 23 chromosomes. The Y axis shows the log-P-value indicating the strength of correlation between the genetic variant and the behavioral outcome (SumQMS4). (B) QQ plot showing the observed and expected association values are free from confounding population stratification.

FIGURE 4

Locus zoom showing associated and flanking regions in (A) 3p25.2, (B) 6p12.1 and (C) 14q24.2, where more than one SNP met the criteria for suggestive association. Genes located within and flanking each of the three regions are indicated below each panel.