Autism Risk Allele in PLAUR Is Associated with Reduced Structural Connectivity in ASD

Background: Multiple genes in the MET receptor tyrosine kinase (MET) signaling pathway have been linked to autism spectrum disorder (ASD) susceptibility (Campbell, 2008); however, the mechanisms by which variation in these genes predispose individuals to ASD remains unclear. We recently found that a common functional variant in MET (rs1858830) is related to reductions in structural and functional connectivity in ASD (Rudie et al, Under Review), in line with previous studies characterizing ASD as a disorder marked by structural and functional underconnectivity (Schipul, 2011). Urokinase plasminogen activator receptor (PLAUR) cleaves hepatocyte growth factor, which binds the MET receptor and activates downstream signaling of multiple processes including axon formation and synaptogenesis. A common functional variant in PLAUR (rs344781) was found to be associated with ASD and there was also evidence of a gene-gene interaction between the MET and PLAUR variants such that individuals with both risk alleles were more likely to be diagnosed with ASD (Campbell 2008).

Objectives: While studies have begun to investigate the role of PLAUR in mouse models (Eagleson et al., 2011), the effect of this common variant using in vivo neuroimaging has yet to be examined. Therefore, we sought to explore whether the common autism risk variant in PLAUR impacts structural connectivity in individuals with ASD.

Methods: Forty-nine children with ASD and 39 typically developing (TD) controls matched for gender, age, and IQ were genotyped for PLAUR (rs344781) and underwent a 32 direction Diffusion Tensor Imaging (DTI) scan in a 3T scanner. White matter integrity was measured by quantifying fractional anisotropy (FA) across major white matter tracts using FSL’s Tract Based Spatial Statistics.

Results: When examining the main effect of the PLAUR risk allele on FA collapsed across ASD and TD groups, PLAUR risk was associated with lower FA in several white matter tracts including the splenium of the corpus callosum and the thalamic radiations. Furthermore, when stratifying the risk groups by diagnostic status (TD and ASD), we found that the PLAUR risk allele impacted more tracts in ASD individuals.

Conclusions: Similar to what we previously observed for the MET risk allele, we found that carriers of the PLAUR risk allele exhibited reductions in structural connectivity, and that this effect was more pronounced in individuals with ASD. Our results suggest that multiple genetic risk factors in the MET signaling pathway may predispose to ASD by negatively affecting structural brain connectivity. An imaging genetics approach that utilizes genetic information in conjunction with brain based measures promises to shed new light on the neurobiological underpinnings of complex neuropsychiatric disorders and ultimately inform the development of targeted interventions.