Abstract
We investigated the role of variation in putative psychosis genes coding for elements of the white matter system by examining the contribution of genotypic variation in three single-nucleotide polymorphisms (SNPs) neuregulin 1 (NRG1) SNP8NRG221533, myelin oligodendrocytes glycoprotein (MOG) rs2857766 and CNP (rs2070106) and one haplotype HAPICE (deCODE) to white matter volume in patients with psychotic disorder and their unaffected relatives. Structural magnetic resonance imaging and blood samples for genotyping were collected on 189 participants including patients with schizophrenia (SZ) or bipolar I disorder (BDI), unaffected first-degree relatives of these patients and healthy volunteers. The association of genotypic variation with white matter volume was assessed using voxel-based morphometry in SPM5. The NRG1 SNP and the HAPICE haplotype were associated with abnormal white matter volume in the BDI group in the fornix, cingulum and parahippocampal gyrus circuit. In SZ the NRG1 SNP risk allele was associated with lower white matter volume in the uncinate fasciculus (UF), right inferior longitudinal fasciculus and the anterior limb of the internal capsule. Healthy G-homozygotes of the MOG SNP had greater white matter volume in areas of the brainstem and cerebellum; this relationship was absent in those with a psychotic disorder and the unaffected relatives groups. The CNP SNP did not contribute to white matter volume variation in the diagnostic groups studied. Variation in the genes coding for structural and protective components of myelin are implicated in abnormal white matter volume in the emotion circuitry of the cingulum, fornix, parahippocampal gyrus and UF in psychotic disorders.
Highlights
IntroductionBipolar I disorder (BDI) and schizophrenia (SZ) share a number of common genetic risk loci and susceptibility genes.[1]
Bipolar I disorder (BDI) and schizophrenia (SZ) share a number of common genetic risk loci and susceptibility genes.[1]. Several of these converge on pathways that regulate oligodendrocytes proliferation, assembly, protection and degeneration. These include the genes coding for neuregulin 1 (NRG1)[2] and myelin oligodendrocytes glycoprotein (MOG)[3,4] and in SZ the 20,30 -cyclic nucleotide 30 phosphodiesterase enzyme (E.C. 3.1.4.37, CNPase) genes.[5]
Given the evidence implicating each of these myelination genes in psychotic illness, this study aims to explore whether genotypic variation potentially conferring risk for psychosis was associated in vivo with white matter volume deviation in three groups of individuals at varying levels of genetic risk for psychosis: in those individuals who developed psychotic illness, in their unaffected first-degree relatives who are likely to be carrying susceptibility genes for illness and in healthy volunteers
Summary
Bipolar I disorder (BDI) and schizophrenia (SZ) share a number of common genetic risk loci and susceptibility genes.[1]. NRG1, MOG, CNP and white matter volume in psychotic disorders tyrosine-protein kinase erbB-3 and is involved in axonal myelination,[18,19,20] and NMDA receptor signaling[21] among a number of other functions.[2] In the prefrontal cortex in SZ and BD, altered expression and protein levels of the NRG1-ErbB signaling system have been detected but are not consistent. These reports include increased expression of ErbB4,22 reduced expression of ErbB3, the alpha isoform of NRG1. Was associated in vivo with white matter volume deviation in three groups of individuals at varying levels of genetic risk for psychosis: in those individuals who developed psychotic illness, in their unaffected first-degree relatives who are likely to be carrying susceptibility genes for illness and in healthy volunteers
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