Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia

Abstract

Context: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies.

Objectives: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging.

Design: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia.

Main outcome measures: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping.

Results: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex.

Conclusions: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.

Figure 1

Tests of pairwise linkage disequilibrium between markers within the PCM1gene.

Figure 2

Gray matter differences associated with main effect of schizophrenia. The figure depicts the anatomical locations in red-yellow of significantly (P<.05, corrected) less gray matter volume in groups of patients with schizophrenia (SZ8 and SZ0) relative to matched controls (CON8 and CON0). Data representing group differences are plotted on sagittal (A) and axial (B) sections of a normalized template brain. Distance in millimeters lateral (x coordinate) to the anterior commissure and vertical (z coordinate) to the anterior commissure/posterior commissure line are given at the bottom left corners of these sections. Marked regional foci of gray matter differences are marked as follows: ac indicates anterior cingulate; dmpfc, dorsal medial prefrontal cortex; ofc, orbitofrontal cortex; th,thalamus; oc, occipital cortex; hc, hippocampus; ins, insula; and itc, inferiortemporal lobe.

Figure 3

Group differences in regional gray matter. Regional gray matter differences between the group of patients with alleles associated with chromosome 8 schizophrenia (SZ8) and their matched controls (CON8) and between the group of patients with schizophrenia but none of the alleles associated with chromosome 8 schizophrenia (SZ0) and their matched controls (CON0). Separate T contrasts were used to test for differences between SZ8 and CON8 and between SZ0 and CON0. These analyses were constrained using masking to regions showing a significant main effect of schizophrenia. Group data are plotted on axial sections of a normalized template brain scan. Regions showing significant differences (P<.05, corrected) between SZ8 and CON8 subjects are depicted in red, and those between SZ0 and CON0 subjects are shown in blue. The axial sections highlight the different patterns of regional gray matter volume deficit associated with these 2 schizophrenic groups; the orbitofrontal deficits in SZ8 patients and the temporal polar and hippocampal deficit in the SZ0 patients are labeled. The distance anterior in millimeters (y coordinate) from the anterior commissure is given in the bottom left corner of each section. ofc indicates orbitofrontal cortex; tp, temporal pole; and hc, hippocampus.

Figure 4

Between-group gray matter differences in orbitofrontal cortex and temporal pole. A, Orbitofrontal gray matter volume deficit in the group of patients with PCM1 alleles associated with chromosome 8 schizophrenia (SZ8), showing involvement of the olfactory gyrus. Adjacent and to the right are plotted the effect sizes of the different parameter estimates. This is given in arbitrary units proportional to the percentage difference in volume-adjusted signal. It is the relative differences rather than the scaling of these values that is the key metric. A, There was relative reduction in orbitofrontal gray matter (at location x, y, z; −7.5, 34.5, −22.5) in both the SZ8 group and the group of patients with schizophrenia with none of the chromosome 8 PCM1 alleles (SZ0). However, the difference was marked for the SZ8 patients, reaching significance for an interaction, (CON8—SZ8) — (CON0—SZ0). B, Temporal pole gray matter volume deficit in SZ0 patients. Locations of gray matter differences between SZ0 patients and other subjects are illustrated on sagittal and axial sections of a template brain. Adjacent is a plot of parameter estimates for the peak of these differences at the left temporal pole. The greater difference in temporal lobe gray matter volume existed between SZ0 and CON0 subjects. The interaction, (CON0—SZ8)—(CON8—SZ8), was significant. CON8 indicates research subjects who are normal controls matched to the SZ8 cases; CON0, research subjects who are normal controls matched to the SZ0 cases.

Figure 5

Map of putative chromosome 8p21-22 schizophrenia susceptibility loci on 8p and diagram of the genomic structure of PCM1 showing the relative positions of exons, introns, and genetic markers. Distances are shown in megabases of DNA. PCM1 indicates pericentriolar material 1; PPP3CC, calcineurin; DRP2, dihydropyrimidinase-related protein 2; FZD3, frizzled; and NRG1 , neuregulin.