Polymorphism within a Neuronal Activity-Dependent Enhancer of NgR1 Is Associated with Corpus Callosum Morphology in Humans

Abstract

The human Nogo-66 receptor 1 (NgR1) gene, also termed Nogo receptor 1 or reticulon 4 receptor (RTN4R) and located within 22q11.2, inhibits axonal growth and synaptic plasticity. Patients with the 22q11.2 deletion syndrome show multiple changes in brain morphology, with corpus callosum (CC) abnormalities being among the most prominent and frequently reported. Thus, we hypothesized that, in humans, NgR1 may be involved in CC formation. We focused on rs701428, a single nucleotide polymorphism of NgR1, which is associated with schizophrenia. We investigated the effects of the rs701428 genotype on CC structure in 50 healthy participants using magnetic resonance imaging. Polymorphism of rs701428 was associated with CC structural variation in healthy participants; specifically, minor A allele carriers had larger whole CC volumes and lower radial diffusivity in the central CC region compared with major G allele homozygous participants. Furthermore, we showed that the NgR1 3′ region, which contains rs701428, is a neuronal activity-dependent enhancer, and that the minor A allele of rs701428 is susceptible to regulation of enhancer activity by MYBL2. Our results suggest that NgR1 can influence the macro- and microstructure of the white matter of the human brain.