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Hugh M. D. Gurling, MBBS, MD, MPhil, FRCPsych; Hugo Critchley, MB, ChB, DPhil, MRCPsych; Susmita R. Datta, BSc; Andrew McQuillin, PhD; Ekaterina Blaveri, PhD; Srinivasa Thirumalai, MD, MRCPsych; Jonathan Pimm, MPhil, MBBS, MRCPsych; Robert Krasucki, BSc, MBBS, MRCPsych; Gursharan Kalsi, PhD; Digby Quested, MD, MRCPsych; Jacob Lawrence, MBBS, BSc, MRCPsych; Nicholas Bass, MB, ChB, BSc, MRCPsych; Khalid Choudhury, BSc; Vinay Puri, BSc; Owen O’Daly, BSc; David Curtis, MBBS, MD, PhD, MRCPsych; Douglas Blackwood, PhD, MRCPsych; Walter Muir, PhD, MRCPsych; Anil K. Malhotra, MD, PhD; Robert W. Buchanan, MD; Catriona D. Good, MB, ChB, FFRad, FRCR; Richard S. J. Frackowiak, MD, DSc, FRCP, FMedSci; Raymond J. Dolan, MD, FRCPsych, FMedSci

Arch Gen Psychiatry. 2006;63:844-854.

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.

Author Affiliations: Molecular Psychiatry Laboratory, Department of Mental Health Sciences, University College London Medical School, Windeyer Institute of Medical Sciences, London, United Kingdom (Drs Gurling, Datta, McQuillin, Blaveri, Pimm, Krasucki, Kalsi, Lawrence, Bass, Choudhury, Puri, and O’Daly); Functional Imaging Laboratory, Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London (Drs Buchanan, Critchley, Good, Frackowiak, and Dolan); Berkshire Healthcare National Health Service Trust, Reading, United Kingdom (Dr Thirumalai); Camden and Islington Mental Health and Social Care Trust, St Pancras Hospital, London; West London Mental Health Trust, Hammersmith and Fulham Mental Health Unit, St Bernard's Hospital, London (Dr Quested); Queen Mary College, University of London and East London and City Mental Health Trust, Royal London Hospital, Whitechapel, London (Dr Curtis); Department of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Scotland, United Kingdom (Drs Blackwood and Muir); Experimental Therapeutics Branch of the National Institute of Mental Health, Bethesda, Md (Dr Malhotra); Maryland Psychiatric Research Center of the University of Maryland School of Medicine, Baltimore (Dr Buchanan); Departement des Etudes Cognitives, Ecole Normale Superieure, Paris, France (Dr Frackowiak). Dr Quested is currently with the Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford, United Kingdom. Dr Malhotra is currently with Psychiatry Research, Hillside Hospital of Long Island Jewish Medical Center, Glen Oaks, New York.

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Gene–Brain Structure Relationships: Arbitrary Assumptions of Heterogeneity Generate Unfalsifiable Claims
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