Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes.

CONTEXT For more than a century, it has been uncertain whether or not the major diagnostic categories of psychosis--schizophrenia and bipolar disorder--are distinct disease entities with specific genetic causes and neuroanatomical substrates. OBJECTIVE To investigate the relationship between genetic risk and structural variation throughout the entire brain in patients and their unaffected relatives sampled from multiply affected families with schizophrenia or bipolar disorder. DESIGN Analysis of the association between genetic risk and variation in tissue volume on magnetic resonance images. SETTING Psychiatric research center. PARTICIPANTS Subjects comprised 25 patients with schizophrenia, 36 of their unaffected first-degree relatives, 37 patients with bipolar 1 disorder who experienced psychotic symptoms during illness exacerbation, and 50 of their unaffected first-degree relatives. MAIN OUTCOME MEASURES We used computational morphometric techniques to map significant associations between a continuous measure of genetic liability for each subject and variation in gray or white matter volume. RESULTS Genetic risk for schizophrenia was specifically associated with distributed gray matter volume deficits in the bilateral fronto-striato-thalamic and left lateral temporal regions, whereas genetic risk for bipolar disorder was specifically associated with gray matter deficits only in the right anterior cingulate gyrus and ventral striatum. A generic association between genetic risk for both disorders and white matter volume reduction in the left frontal and temporoparietal regions was consistent with left frontotemporal disconnectivity as a genetically controlled brain structural abnormality common to both psychotic disorders. CONCLUSIONS Genetic risks for schizophrenia and bipolar disorder are associated with specific gray matter but generic white matter endophenotypes. Thus, Emil Kraepelin's pivotal distinction was neither wholly right nor wholly wrong: the 2 major psychoses show both distinctive and similar patterns of brain structural abnormality related to variable genetic risk.

[1]  J. Avery.  Critical review. , 2006, The Journal of the Arkansas Medical Society.

[2]  E. Bullmore,et al.  Permutation tests for factorially designed neuroimaging experiments , 2004, Human brain mapping.

[3]  Marieke Langen,et al.  Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia , 2004, Biological Psychiatry.

[4]  Tyrone D. Cannon,et al.  Reduced left hemispheric white matter volume in twins with bipolar I disorder , 2003, Biological Psychiatry.

[5]  Peter B. Jones,et al.  Oligodendrocyte dysfunction in schizophrenia and bipolar disorder , 2003, The Lancet.

[6]  P. Sham,et al.  The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. , 2003, Archives of general psychiatry.

[7]  Philip D. Harvey,et al.  White matter changes in schizophrenia: evidence for myelin-related dysfunction. , 2003, Archives of general psychiatry.

[8]  T. Sigmundsson,et al.  Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives , 2003, Biological Psychiatry.

[9]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[10]  John Suckling,et al.  For personal use. Only reproduce with permission from The Lancet Publishing Group. Effect of sunlight and season on serotonin turnover in the brain , 2002 .

[11]  Stephen M Strakowski,et al.  Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. , 2002, The American journal of psychiatry.

[12]  Oili Salonen,et al.  Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. , 2002, The American journal of psychiatry.

[13]  Nikos Makris,et al.  Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. , 2002, Archives of general psychiatry.

[14]  Muriel Walshe,et al.  Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives. , 2002, American journal of medical genetics.

[15]  R. Murray,et al.  Schizophrenia and bipolar disorder: similarities in pathogenic mechanisms but differences in neurodevelopment. , 2002, International clinical psychopharmacology.

[16]  J. Simon,et al.  Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia , 2002, Schizophrenia Research.

[17]  Tyrone D. Cannon,et al.  Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Alan C. Evans,et al.  Focal gray matter density changes in schizophrenia. , 2001, Archives of general psychiatry.

[19]  Karl J. Friston,et al.  A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains , 2001, NeuroImage.

[20]  R. Bilder.  “The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review”– by CE Bearden, KM Hoffman and TD Cannon: a commentary , 2001 .

[21]  Tyrone D. Cannon,et al.  The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. , 2001, Bipolar disorders.

[22]  S. Torgersen,et al.  The prevalence of personality disorders in a community sample. , 2001, Archives of general psychiatry.

[23]  S. Lawrie,et al.  Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia , 2001, Biological Psychiatry.

[24]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  T. Sigmundsson,et al.  Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. , 2001, The American journal of psychiatry.

[26]  G. Bartzokis,et al.  An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia , 2000, Biological Psychiatry.

[27]  Karl J. Friston,et al.  Voxel-Based Morphometry—The Methods , 2000, NeuroImage.

[28]  R S Kahn,et al.  Structural brain abnormalities in patients with schizophrenia and their healthy siblings. , 2000, The American journal of psychiatry.

[29]  R. Murray,et al.  Early and late environmental risk factors for schizophrenia , 2000, Brain Research Reviews.

[30]  D. Weinberger,et al.  Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. , 2000, The American journal of psychiatry.

[31]  R. Murray,et al.  Meta-analysis of regional brain volumes in schizophrenia. , 2000, The American journal of psychiatry.

[32]  K. O Lim,et al.  Cortical gray matter deficit in patients with bipolar disorder , 1999, Schizophrenia Research.

[33]  Nikos Makris,et al.  Thalamic and amygdala–hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis , 1999, Biological Psychiatry.

[34]  M. Posner.  The Brain and Emotion , 1999, Nature Medicine.

[35]  R. McCarley,et al.  MRI anatomy of schizophrenia , 1999, Biological Psychiatry.

[36]  K. Krishnan,et al.  Hyperintense lesions on magnetic resonance images in bipolar disorder , 1999, Biological Psychiatry.

[37]  A. D. de Crespigny,et al.  Compromised white matter tract integrity in schizophrenia inferred from diffusion tensor imaging. , 1999, Archives of general psychiatry.

[38]  R. Murray,et al.  Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. , 1999, Archives of general psychiatry.

[39]  C. Pantelis,et al.  Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. , 1999, Archives of general psychiatry.

[40]  Eve C Johnstone,et al.  Magnetic resonance imaging of brain in people at high risk of developing schizophrenia , 1999, The Lancet.

[41]  John Suckling,et al.  Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain , 1999, IEEE Transactions on Medical Imaging.

[42]  R S Kahn,et al.  Partial volume decrease of the thalamus in relatives of patients with schizophrenia. , 1998, The American journal of psychiatry.

[43]  O Salonen,et al.  Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. , 1998, Archives of general psychiatry.

[44]  Tyrone D. Cannon,et al.  The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study. , 1998, Archives of general psychiatry.

[45]  S. Paradiso,et al.  "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? , 1998, Schizophrenia bulletin.

[46]  R. Murray,et al.  The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia , 1997, Schizophrenia Research.

[47]  R. Langevin,et al.  Deficits in gray matter volume are present in schizophrenia but not bipolar disorder 1 This work was presented at the Meeting of the Society of Biological Psychiatry, Philadelphia, PA, USA, May 1994. 1 , 1997, Schizophrenia Research.

[48]  M. Raichle,et al.  Subgenual prefrontal cortex abnormalities in mood disorders , 1997, Nature.

[49]  G. Pearlson,et al.  Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder , 1997, Biological Psychiatry.

[50]  Robin M. Murray,et al.  Can biological markers identify endophenotypes predisposing to schizophrenia , 1997 .

[51]  L. Altshuler,et al.  T2 hyperintensities in bipolar disorder: magnetic resonance imaging comparison and literature meta-analysis. , 1995, The American journal of psychiatry.

[52]  Karl J. Friston,et al.  Schizophrenia: a disconnection syndrome? , 1995, Clinical neuroscience.

[53]  K. Kendler,et al.  Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish Adoption Study of Schizophrenia. , 1994, Archives of general psychiatry.

[54]  T. Goldberg,et al.  The frontal lobes and schizophrenia. , 1994, The Journal of neuropsychiatry and clinical neurosciences.

[55]  F. Goodwin,et al.  The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. , 1993, Archives of general psychiatry.

[56]  F. Vogel,et al.  Schizophrenia genesis: The origins of madness , 1991 .

[57]  M. Torrens.  Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[58]  R. Murray,et al.  Is schizophrenia a neurodevelopmental disorder? , 1987, British medical journal.

[59]  S. Kety,et al.  Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders. , 1986, Archives of general psychiatry.

[60]  D. Klein,et al.  Schedule for Affective Disorders and Schizophrenia--Lifetime Version modified for the study of anxiety disorders (SADS-LA): rationale and conceptual development. , 1986, Journal of psychiatric research.

[61]  M. Baron,et al.  The Schedule for Schizotypal Personalities (SSP): A diagnostic interview for schizotypal features , 1981, Psychiatry Research.

[62]  N. L. Johnson,et al.  Multivariate Analysis , 1958, Nature.