Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia.
BACKGROUND
There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies.


OBJECTIVE
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.


METHODS
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.


METHODS
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.
Gurling
Hugh M D
HM
Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, United Kingdom. h.gurling@ucl.ac.uk
Critchley
Hugo
H
Datta
Susmita R
SR
McQuillin
Andrew
A
Blaveri
Ekaterina
E
Thirumalai
Srinivasa
S
Pimm
Jonathan
J
Krasucki
Robert
R
Kalsi
Gursharan
G
Quested
Digby
D
Lawrence
Jacob
J
Bass
Nicholas
N
Choudhury
Khalid
K
Puri
Vinay
V
O'Daly
Owen
O
Curtis
David
D
Blackwood
Douglas
D
Muir
Walter
W
Malhotra
Anil K
AK
Buchanan
Robert W
RW
Good
Catriona D
CD
Frackowiak
Richard S J
RS
Dolan
Raymond J
RJ
D000328:Adult; D000483:Alleles; D001284:Atrophy / Q000473:pathology; D001324:Autoantigens / Q000235:genetics*; D001921:Brain / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics*; D018385:Centrosome / Q000378:metabolism / Q000473:pathology*; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008279:Magnetic Resonance Imaging; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000235:genetics*
D001324:Autoantigens; D018797:Cell Cycle Proteins; D005819:Genetic Markers; C086074:PCM1 protein, human