Influence of genes and environment on brain volumes in twin pairs concordant and discordant for bipolar disorder.

CONTEXT Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown. OBJECTIVE To investigate the contribution of genetic and environmental factors on brain volume in bipolar disorder. DESIGN Magnetic resonance imaging (1.5 T) brain scans of monozygotic (MZ) or dizygotic (DZ) twins concordant and discordant for bipolar disorder were compared with healthy twin pairs. SETTING Subjects were recruited from the population, the Netherlands Twin Register, and the twin pair cohort at the University Medical Center Utrecht, Utrecht, The Netherlands. PARTICIPANTS A total of 234 subjects including 50 affected twin pairs (9 MZ concordant; 15 MZ discordant; 4 DZ concordant; 22 DZ discordant) and 67 healthy twin pairs (39 MZ and 28 DZ) were included. MAIN OUTCOME MEASURES Volumes of the intracranium, cerebrum, cerebellum, lateral and third ventricle, and gray and white matter from the cerebrum and frontal, parietal, temporal, and occipital lobes, both with and without correction for lithium use. To estimate the influence of additive genetic, common, and unique environmental factors, structural equation modeling was applied. RESULTS Bipolar disorder was associated with a decrease in total cortical volume. Decreases in white matter were related to the genetic risk of developing bipolar disorder (bivariate heritability, 77%; 95% confidence interval, 38% to 100%). Significant environmental correlations were found for cortical gray matter. These relationships all became more pronounced when data were corrected for lithium use. CONCLUSIONS Focusing on genes controlling white matter integrity may be a fruitful strategy in the quest to discover genes implicated in bipolar disorder. Elucidating the mechanism by which lithium attenuates brain matter loss may lead to the development of neuroprotective drugs.

[1]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[2]  R. C. Young,et al.  A Rating Scale for Mania: Reliability, Validity and Sensitivity , 1978, British Journal of Psychiatry.

[3]  B. Woods,et al.  Structural brain abnormalities in first-episode mania , 1993, Biological Psychiatry.

[4]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[5]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[6]  G. Pearlson,et al.  Decreased regional cortical gray matter volume in schizophrenia. , 1994, The American journal of psychiatry.

[7]  L. Friedman,et al.  Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Comparisons with controls or patients with schizophrenia. , 1995, Archives of general psychiatry.

[8]  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.

[9]  Michael C. Neale,et al.  The Use of Likelihood-Based Confidence Intervals in Genetic Models , 1997, Behavior genetics.

[10]  B. Mowry,et al.  Structured interview for DSM-IV personality: SIDP-IV , 1998 .

[11]  J. Price,et al.  Glial reduction in the subgenual prefrontal cortex in mood disorders. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

[13]  N. Craddock,et al.  Genetics of bipolar disorder. , 2010, Journal of medical genetics.

[14]  H. Manji,et al.  The Mood‐Stabilizing Agents Lithium and Valproate RobustlIncrease the Levels of the Neuroprotective Protein bcl‐2 in the CNS , 1999, Journal of neurochemistry.

[15]  G. Moore,et al.  Lithium-induced increase in human brain grey matter , 2000, The Lancet.

[16]  Guang Chen,et al.  Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? , 2000, Biological Psychiatry.

[17]  R. Kahn,et al.  Automated Separation of Gray and White Matter from MR Images of the Human Brain , 2001, NeuroImage.

[18]  J. Noga,et al.  A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder , 2001, Psychiatry Research: Neuroimaging.

[19]  R. S. Kahn,et al.  Automatic Segmentation of the Ventricular System from MR Images of the Human Brain , 2001, NeuroImage.

[20]  N. Craddock,et al.  Molecular genetics of bipolar disorder. , 2001, The British journal of psychiatry : the journal of mental science.

[21]  R. Kahn,et al.  Quantitative genetic modeling of variation in human brain morphology. , 2001, Cerebral cortex.

[22]  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.

[23]  D. Kupfer,et al.  Differential Effects of Age on Brain Gray Matter in Bipolar Patients and Healthy Individuals , 2001, Neuropsychobiology.

[24]  D. Kupfer,et al.  Increased gray matter volume in lithium-treated bipolar disorder patients , 2002, Neuroscience Letters.

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

[26]  Pak Chung Sham,et al.  Analytic approaches to twin data using structural equation models , 2002, Briefings Bioinform..

[27]  W. Nolen,et al.  Bipolar disorder in the general population in The Netherlands (prevalence, consequences and care utilisation): results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). , 2002, Journal of affective disorders.

[28]  S. Strakowski,et al.  Regional prefrontal gray and white matter abnormalities in bipolar disorder , 2002, Biological Psychiatry.

[29]  G. Rajkowska.  Cell pathology in bipolar disorder. , 2002, Bipolar disorders.

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

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

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

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

[34]  N. Uranova,et al.  Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium , 2004, Schizophrenia Research.

[35]  E. Bramon,et al.  Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. , 2004, Archives of general psychiatry.

[36]  V. Cardenas,et al.  Decreased cortical gray and cerebral white matter in male patients with familial bipolar I disorder. , 2004, Journal of affective disorders.

[37]  W. Nolen,et al.  Prevalence of bipolar disorder in the general population: a Reappraisal Study of the Netherlands Mental Health Survey and Incidence Study , 2004, Acta psychiatrica Scandinavica.

[38]  Sophia Rabe-Hesketh,et al.  Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder , 2004, Biological Psychiatry.

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

[40]  S. Strakowski,et al.  Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. , 2004, Bipolar disorders.

[41]  Joost Janssen,et al.  Larger Brains in Medication Naive High-Functioning Subjects with Pervasive Developmental Disorder , 2004, Journal of autism and developmental disorders.

[42]  T. Whitford,et al.  Diagnosis-Related Regional Gray Matter Loss Over Two Years in First Episode Schizophrenia and Bipolar Disorder , 2005, Biological Psychiatry.

[43]  Cheuk Y. Tang,et al.  Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses , 2005, Biological Psychiatry.

[44]  J. Potash,et al.  Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: A pilot study , 2005, Biological Psychiatry.

[45]  E. Leibenluft,et al.  Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. , 2005, Archives of general psychiatry.

[46]  T Toulopoulou,et al.  Brain MRI abnormalities in schizophrenia: same genes or same environment? , 2005, Psychological Medicine.

[47]  Muriel Walshe,et al.  Regional volume deviations of brain structure in schizophrenia and psychotic bipolar disorder , 2005, British Journal of Psychiatry.

[48]  S. Strakowski,et al.  Changes in Gray Matter Volume in Patients with Bipolar Disorder , 2005, Biological Psychiatry.

[49]  E. Bramon,et al.  Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives. , 2006, The American journal of psychiatry.

[50]  Gustavo Turecki,et al.  Genome wide gene expression studies in mood disorders. , 2006, Omics : a journal of integrative biology.

[51]  N. Uranova,et al.  Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders , 2007, Schizophrenia Research.

[52]  Kilian M. Pohl,et al.  Neocortical Gray Matter Volume in First-Episode Schizophrenia and First-Episode Affective Psychosis: A Cross-Sectional and Longitudinal MRI Study , 2007, Biological Psychiatry.

[53]  C. Carter,et al.  eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? , 2006, Schizophrenia bulletin.

[54]  B. Sokolov,et al.  Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies? , 2007, The international journal of neuropsychopharmacology.

[55]  S. Lawrie,et al.  Progressive Gray Matter Loss in Patients with Bipolar Disorder , 2007, Biological Psychiatry.

[56]  C. Carter.  Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: Implications for oligodendrocyte viability , 2007, Neurochemistry International.

[57]  E. Bramon,et al.  Substantial shared genetic influences on schizophrenia and event-related potentials. , 2007, The American journal of psychiatry.

[58]  P. Hof,et al.  Oligodendrocyte pathophysiology: a new view of schizophrenia. , 2007, The international journal of neuropsychopharmacology.

[59]  Kiralee M. Hayashi,et al.  Greater Cortical Gray Matter Density in Lithium-Treated Patients with Bipolar Disorder , 2007, Biological Psychiatry.

[60]  Glenda M MacQueen,et al.  Bilateral Hippocampal Volume Increase in Patients with Bipolar Disorder and Short-term Lithium Treatment , 2008, Neuropsychopharmacology.

[61]  Patrick Royston,et al.  Development and validation of an international risk prediction algorithm for episodes of major depression in general practice attendees: the PredictD study. , 2008, Archives of general psychiatry.

[62]  James J Levitt,et al.  A cross-sectional and longitudinal magnetic resonance imaging study of cingulate gyrus gray matter volume abnormalities in first-episode schizophrenia and first-episode affective psychosis. , 2008, Archives of general psychiatry.