The major finding from this study is the association between genotypic variation in NRG, previously linked to psychotic illness, and white matter abnormalities in psychotic patients and their relatives. Individuals with SZ and carrying the risk allele C, of the NRG1 SNP8NRG221533, had lower white matter volume in the regions of the right uncinate fasciculus, right inferior longitudinal fasciculus and in the ALIC (overlapping portions of the anterior thalamic radiations and the corticopontine tracts). Unaffected relatives of patients with SZ possessing at least one copy of the HAPICE haplotype had less white matter volume in the fornix and superior cerebellar peduncle compared with those with no copies. In contrast, those BD1 patients carrying the NRG risk allele C of SNP8NRG221533 had greater white matter volume in the posterior cingulum/parahippocampal gyrus and a number of regions of the corpus callosum. Similarly, individuals with BDI and at least one copy of the HAPICE haplotype, which includes the risk allele of the NRG1 SNP8NRG221533, possessed greater white matter volume in the cingulum and fornix.
There was no association between white matter volume and genotypic variation in SNP8NRG221533 in healthy volunteers, consistent with the study by Winterer et al
using a similar voxel-based approach (optimized VBM and SPM5). However, Winterer et al.34
did detect reduced medial frontal FA using diffusion tensor imaging in C-carriers of the SNP8NRG221533. McIntosh et al.36
have additionally reported reduced white matter density and FA in the ALIC associated with the TT-genotype of another NRG1
SNP in the promoter region of the gene (SNP8NRG243177). Finally, the NRG1
gene SNP and exact population studied herein has been examined previously for contribution to variance in the volume of the lateral ventricles or hippocampus and no relationship was detected.82
The present finding implicates the NRG1
gene SNP, SNP8NRG221533 in white matter-related abnormalities of the emotion circuitry in BD,83
and in previously implicated regions in SZ including the ALIC. It is not clear why in contrast to the SZ group, the SZ risk genotype is associated with increased white matter in the cingulum and corpus callosum in the BDI group. These data suggest the possibility that another currently unknown factor associated with having BDI may be involved in modulating the relationship between the NRG1
SNP genotype and white matter volume. In addition, long-term antipsychotic medication exposure may mediate structural changes as has been recently demonstrated.84
Thus, it remains possible that in the SZ group, an as yet unidentified, interaction between genotype and medication response may contribute to the present findings.
Several models of the neurocircuitry underlying psychiatric disorders have been developed many based on structural and functional evidence from in vivo
neuroimaging studies. These and similar recent studies33, 36, 37, 85, 86, 87
substantiate a growing body of evidence implicating genetic susceptibility to developing abnormalities within and between (white matter volume and microstructural organization) emotion-related structures. These studies collectively contribute to progress toward the inevitable future clinical application of such in vivo
knowledge, which may include earlier detection of susceptibility, monitoring progression, presaging treatment response and potentially diagnosing based classification.88
It is not known whether MOG
rs2857766 confers risk for SZ or BD and, in our study we found no relationship between genotype and white matter volume in the brain in these groups. However, we provide preliminary evidence suggesting a possible relationship between G-homozygosity (the ancestral allele) in MOG
rs2857766 and greater brainstem level white matter volume in psychiatrically healthy individuals that was not detected in psychotic patients or their unaffected relatives. The uniformity of microstructural organization of white matter in this region, the middle cerebellar peduncle has been reported to be disrupted in SZ using diffusion-weighted imaging.89
However, there is insufficient evidence to directly implicate MOG
rs2857766 in disruption of the middle cerebellar peduncle.
Despite previous reports of the involvement of CNPase SNP rs2070106 in SZ and BD, this study did not detect any relationship between white matter volume and genetic variation in this SNP in any patient or relative group examined or among the healthy controls.
Individual SNPs are unlikely to confer more than a relatively minor proportion of variation in white matter volume, however, such associations may serve to highlight biological processes that are involved in dysfunctional white matter circuits and point to other genetic variants or functional units that are tightly linked to such pathophysiology and that warrant further exploration. A limitation of this study is the small number of subjects in some of the genotype groups and it is possible we were underpowered to detect relationships with white matter that may be detected in the future with more sensitive technology, analysis methods and larger cohorts of subjects. In addition, the inclusion of a related pairs of individuals within the unaffected SZ and BD relative groups to preserve power represents a limitation of this study. Despite their inclusion, however, no positive finding was detected for any genotype examined in the unaffected BD group or for three of the four genotypes examined in the case of the unaffected SZ group. In the unaffected SZ group, those having one or two copies of the HAPICE
haplotype showed a trend toward lower white matter volume in the superior cerebellar peduncle and the fornix relative to those with no copies. Removing all related individuals from this group did not significantly alter the magnitude or direction of this finding. A particular limitation of the voxel-based approach to image analysis is the possibility of errors due to registration and segmentation steps.77
To minimize these possible sources of error, registration and segmentation performance were visually assessed on an individual basis. A particular strength of this study was the inclusion of subjects who were unaffected but had a relative with a psychotic disorder. In the case of the MOG
SNP examined, the absence in all affected groups and their relatives of the relationship detected in healthy controls suggests a possible pathological role for this SNP in psychotic disorders. Future linkage, case–control, family and genome-wide studies may further elucidate the role of this MOG
SNP in psychosis.
In summary, these findings provide support for the theory that genotypic variation in neuregulin may confer risk for psychosis by influencing white matter in areas known to underlie the emotional circuitry of the human brain.83
The deficits in white matter volume detected in this study have a number of possible underlying explanations including reduced axonal projections or a reduction in the volume of non-axonal white matter components including glia. An optimum ratio of axonal diameter to myelin sheath thickness termed the g-ratio has been described in terms of efficiency of conductivity.90, 91
It is plausible that regional perturbations of this ratio may manifest as signs and symptoms associated with psychotic disorders.92
Volume changes in white matter are inherently limited in forming the nature or identity of molecular factors involved in abnormalities detected, and future studies examining the uniformity of microstructural organization of white matter using diffusion-weighted MR imaging with genotype among other approaches will aid in the identification of the mechanism by which the NRG risk allele contributes to the signs and symptoms of psychotic disorders.