A voxel-based morphometric study about the effects of susceptibility genes for schizophrenia on grey matter volumes

DieThe etiology of schizophrenia and other psychiatric disorders is characterized by a strong genetic influence which was confirmed in family, twin and adoption studies. Within genome wide coupling and association studies certain chromosomal regions with an increased risk for psychiatric diseases, in particular for schizophrenia, could be discovered, such as the susceptibility genes DTNBP-1, NRG-1, DISC-1 and G72. Certain allelic variations of these genes, so-called SNP (single nucleotide polymorphisms), are associated with an increased risk for the disorder. These susceptibility genes are believed to influence brain regional volumes of grey matter. Hippocampal volume reduction is one of the major neuropathological findings in schizophrenia. Further so-called endophenotypes are reduced volume of temporal lobes, frontal lobes, ventrolateral prefrontal cortex (VLPFC) as well as dorsolateral prefrontal cortex (DLPFC). In the present study 161 patients with schizophrenia (n= 44), bipolar disorder (n= 42), compulsive disorder (n= 31) as well as a healthy control group (n= 44) were examined. All study participants were genotyped with respect to the single nucleotide polymorphisms and submitted to imaging of T1-weighted MRI on a 1,5 Tesla system. The analysis of the images was carried out using voxel-based morphometry (VBM). The statistical evaluation was based on SPM5 (statistical parametric mapping). According to the previous findings, structural changes of grey matter were found in region of hippocampus, frontal and temporal lobes and other structures. Interestingly, the risk SNP of all examined susceptibility genes showed an increased grey matter volume instead of volume deficits. In DTNBP-1 the SNP rs2619522 (P1763) with the risk allele guanine and the SNP rs1018381 (P1578) with the allele thymine were examined. In both gene variants, volume alterations were found in the left hippocampus, the frontal and temporal cortex. Effects of frontal and temporal increased grey matter volumes were found in the SNP rs4733263 of the risk gene NRG-1 with respect to the guanine variant. The risk allele adenine encoding for the amino acid serine in the SNP rs821616 (exon11 / ser704cys) of the DISC-1 is responsible for alterations of the frontal and temporal cortex. The risk gene G72 with regard to the SNP rs1935058 and the cytosine variant is associated with grey matter changes in area of left hippocampus, frontal and temporal lobe. With respect of the SNP rs778294 (M19) an increased grey matter volume in the region of frontal and temporal lobe can be found in carriers of the risk allele thymine. In contrast to prior findings this study shows an increase of grey matter volume. While this might be compensatory due to disturbed feedback-loops, it could also reflect a relative volume increase due to a mismatch between grey and white matter. Chronic neuroleptic medication has also been described to cause this effect. It seems likely that the multifactorial etiology of schizophrenia with its genetic heterogeneity is reflected in a large variety of phenotypes- not only with regard to clinical presentation but also in terms of morphologic alterations at the CNS level