The effects of a neuregulin 1 variant on white matter density and integrity

Abstract

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T 1 -weighted MRI) and integrity (DTI) was ascertained. Subjects with the riskassociated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

The relationship of anterior thalamic radiation integrity to psychosis risk associated neuregulin-1 variants

“…As the SNPs are in strong linkage disequilibrium, it is possible that both are indexing the same genetic effect. Although previous voxel-wise FA analyses have localized the effects of these SNPs to seemingly different anatomical regions, 6,7 the present data demonstrate that these effects may be common to a specific tract, the ATR.…”

“…3 Neuregulin-1 (NRG1) is a gene associated with risk for schizophrenia 4 and bipolar disorder 5 as well as with white matter density and integrity in the medial prefrontal cortex 6 and the ALIC. 7 In this study, tractography reveals that these NRG1 effects can also be localized to the ATR.…”

ErbB4 Genotype Predicts Left Frontotemporal Structural Connectivity in Human Brain

“…At the same time, our finding that the schizophrenia risk genotype predicts RT in the expected direction largely concurs with another study, which has reported ErbB4 genotype effects on neurocognitive measures in healthy controls (Nicodemus et al, 2006). The impact of schizophrenia risk NRG1 ErbB4 effects on left frontotemporal connectivity A Konrad et al genotypes on human WM has been shown in two DTI studies (McIntosh et al, 2007;Winterer et al, 2008). Therefore, our findings provide additional support for the notion that variations of the NRG1/ErbB4 signaling pathway might indeed be relevant for neuronal myelination.…”

“…Two recent diffusion tensor imaging (DTI) studies have reported schizophrenia risk NRG1 genotype effects on WM microstructure in human brain (McIntosh et al, 2007;Winterer et al, 2008). These studies thus support the notion that variations of the NRG1 gene might indeed be relevant for neuronal myelination as fractional anisotropy (FA) is thought to be an index of the degree of neuronal myelination (Davis et al, 2003).…”

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

“…[5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage. These isoforms are divided into three classic groups: 10 type I (previously known as acetylcholine receptor inducing activity, heregulin or neu differentiation factor), type II (glia growth factor) and type III (cysteine-rich domain containing), which are based on distinct amino termini.…”