Genome-wide supported risk variant for bipolar disorder alters anatomical connectivity in the human brain

Bipolar disorder is a devastating, highly heritable mental disorder related to disturbed connectivity between limbic and frontal brain areas. A meta-analysis of genome-wide association studies as well as independent replications showed ankyrin 3 (ANK3) to be one of the best-supported risk genes for bipolar disorder. Using an imaging genetics approach employing diffusion tensor imaging in 88 healthy volunteers, we show decreased white matter integrity, indicated by lower fractional anisotropy and longitudinal diffusivity, in healthy carriers of the ANK3 rs10994336 risk genotype in the anterior limb of the internal capsule. We are also able to show that the resulting alterations of cortical-striatal-thalamic circuits are related to impaired set-shifting and increased risk-taking. For risk-allele carriers of ANK3 rs9804190 no white matter alterations or neuropsychological impairments were observed. In sum, our findings show that ANK3 rs10994336 or a variant in linkage-disequilibrium is functional in the human brain and also influences behavioral phenotypes related to bipolar disorder.

[1]  A M McIntosh,et al.  Set shifting and reversal learning in patients with bipolar disorder or schizophrenia , 2008, Psychological Medicine.

[2]  M. F. Luce,et al.  Separate Neural Mechanisms Underlie Choices and Strategic Preferences in Risky Decision Making , 2009, Neuron.

[3]  P. Poulet,et al.  Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging , 2006, Journal of neuroscience research.

[4]  J. Os,et al.  Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives , 2007, Psychological Medicine.

[5]  Khader M Hasan,et al.  Diffusion Tensor Imaging in MDMA Users and Controls: Association with Decision Making , 2007, The American journal of drug and alcohol abuse.

[6]  A. Alexander,et al.  Diffusion tensor imaging of the brain , 2007, Neurotherapeutics.

[7]  H. Axer,et al.  Mapping of fiber orientation in human internal capsule by means of polarized light and confocal scanning laser microscopy , 2000, Journal of Neuroscience Methods.

[8]  H. Axer,et al.  Morphological asymmetry in anterior limb of human internal capsule revealed by confocal laser and polarized light microscopy , 1999, Psychiatry Research: Neuroimaging.

[9]  Stephen M. Smith,et al.  Threshold-free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference , 2009, NeuroImage.

[10]  Mark E. Bastin,et al.  White Matter Integrity in Individuals at High Genetic Risk of Bipolar Disorder , 2011, Biological Psychiatry.

[11]  R. Rogers,et al.  Altered Risk-Aversion and Risk-Seeking Behavior in Bipolar Disorder , 2009, Biological Psychiatry.

[12]  R. Kikinis,et al.  A diffusion tensor imaging study of the anterior limb of the internal capsule in schizophrenia , 2010, Psychiatry Research: Neuroimaging.

[13]  T. Robbins,et al.  Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man , 1991, Neuropsychologia.

[14]  C. Büchel,et al.  Overlapping and Distinct Neural Systems Code for Subjective Value during Intertemporal and Risky Decision Making , 2009, The Journal of Neuroscience.

[15]  B. Sahakian,et al.  Hot and cold cognition in unmedicated depressed subjects with bipolar disorder. , 2009, Bipolar disorders.

[16]  Michele Tansella,et al.  DTI studies of corpus callosum in bipolar disorder. , 2009, Biochemical Society transactions.

[17]  T. Robbins,et al.  Dissociable Deficits in the Decision-Making Cognition of Chronic Amphetamine Abusers, Opiate Abusers, Patients with Focal Damage to Prefrontal Cortex, and Tryptophan-Depleted Normal Volunteers: Evidence for Monoaminergic Mechanisms , 1999, Neuropsychopharmacology.

[18]  Elena Goetz,et al.  Euthymic Patients with Bipolar Disorder Show Decreased Reward Learning in a Probabilistic Reward Task , 2008, Biological Psychiatry.

[19]  Mark Jenkinson,et al.  Combining shape and connectivity analysis: An MRI study of thalamic degeneration in Alzheimer's disease , 2010, NeuroImage.

[20]  Daniel Rueckert,et al.  Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data , 2006, NeuroImage.

[21]  Yong He,et al.  Functional and Structural Connectivity Between the Perigenual Anterior Cingulate and Amygdala in Bipolar Disorder , 2009, Biological Psychiatry.

[22]  Frank Dudbridge,et al.  Likelihood-Based Association Analysis for Nuclear Families and Unrelated Subjects with Missing Genotype Data , 2008, Human Heredity.

[23]  C Poupon,et al.  Increased white matter connectivity in euthymic bipolar patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex , 2007, Molecular Psychiatry.

[24]  M. Wessa,et al.  How to regulate emotion? Neural networks for reappraisal and distraction. , 2011, Cerebral cortex.

[25]  M. Rietschel,et al.  The CACNA1C risk variant for bipolar disorder influences limbic activity , 2010, Molecular Psychiatry.

[26]  E. Bora,et al.  Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. , 2009, Journal of affective disorders.

[27]  R. El-Mallakh,et al.  Bipolar Disorder: An Update , 2010, Postgraduate medicine.

[28]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[29]  J. Ballenger,et al.  Abnormal frontal cortex white matter connections in bipolar disorder: A DTI tractography study , 2012 .

[30]  A. Meyer-Lindenberg,et al.  Intermediate phenotypes and genetic mechanisms of psychiatric disorders , 2006, Nature Reviews Neuroscience.

[31]  Nicholas D. Walsh,et al.  Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics. , 2008, Archives of general psychiatry.

[32]  Manuel A. R. Ferreira,et al.  Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder , 2008, Nature Genetics.

[33]  Allen W. Song,et al.  White matter abnormalities in bipolar disorder: insights from diffusion tensor imaging studies , 2010, Journal of Neural Transmission.

[34]  Larry A. Kramer,et al.  Diffusion Tensor Imaging and Decision Making in Cocaine Dependence , 2010, PloS one.

[35]  S. Cichon,et al.  Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder , 2008, Molecular Psychiatry.

[36]  Cynthia Wilson Garvan,et al.  Diffusion Tensor Imaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children , 2006, Pediatrics.

[37]  L. Clark,et al.  Trait-Related Decision-Making Impairment in the Three Phases of Bipolar Disorder , 2011, Biological Psychiatry.

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

[39]  R. Fisher 014: On the "Probable Error" of a Coefficient of Correlation Deduced from a Small Sample. , 1921 .

[40]  M. Hautzinger,et al.  Allgemeine Depressions Skala , 1993 .

[41]  Sheng-Kwei Song,et al.  Axial Diffusivity Is the Primary Correlate of Axonal Injury in the Experimental Autoimmune Encephalomyelitis Spinal Cord: A Quantitative Pixelwise Analysis , 2009, The Journal of Neuroscience.

[42]  E. Vassos,et al.  The Cognitive Impact of the ANK3 Risk Variant for Bipolar Disorder: Initial Evidence of Selectivity to Signal Detection during Sustained Attention , 2011, PloS one.

[43]  S. Rauch,et al.  Neurobiology of emotion perception II: implications for major psychiatric disorders , 2003, Biological Psychiatry.

[44]  R. Kalisch The functional neuroanatomy of reappraisal: Time matters , 2009, Neuroscience & Biobehavioral Reviews.

[45]  P. Basser,et al.  MR diffusion tensor spectroscopy and imaging. , 1994, Biophysical journal.

[46]  M. First,et al.  Structured Clinical Interview for DSM-IV Axis I Disorders , 1997 .

[47]  Kelvin Lim,et al.  Lower orbital frontal white matter integrity in adolescents with bipolar I disorder. , 2009, Journal of the American Academy of Child and Adolescent Psychiatry.

[48]  Vince D. Calhoun,et al.  An ICA-based method for the identification of optimal FMRI features and components using combined group-discriminative techniques , 2009, NeuroImage.

[49]  D. A. Grant,et al.  A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. , 1948, Journal of experimental psychology.

[50]  M. Rasband,et al.  AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity , 2008, The Journal of cell biology.

[51]  Timothy Edward John Behrens,et al.  Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging , 2003, Nature Neuroscience.

[52]  T. Robbins,et al.  Defining the Neural Mechanisms of Probabilistic Reversal Learning Using Event-Related Functional Magnetic Resonance Imaging , 2002, The Journal of Neuroscience.

[53]  Daniel S Pine,et al.  Deficits on a probabilistic response-reversal task in patients with pediatric bipolar disorder. , 2005, The American journal of psychiatry.

[54]  Eve C. Johnstone,et al.  White Matter Density in Patients with Schizophrenia, Bipolar Disorder and Their Unaffected Relatives , 2005, Biological Psychiatry.

[55]  S. Wakana,et al.  MRI Atlas of Human White Matter , 2005 .

[56]  John Russell,et al.  Dysmyelination Revealed through MRI as Increased Radial (but Unchanged Axial) Diffusion of Water , 2002, NeuroImage.

[57]  M. Leboyer,et al.  Microstructural white matter changes in euthymic bipolar patients : a whole-brain diffusion tensor imaging study , 2009 .

[58]  James McKirdy,et al.  White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging. , 2009, Bipolar disorders.

[59]  Paul M. Thompson,et al.  Genetics of microstructure of cerebral white matter using diffusion tensor imaging , 2010, NeuroImage.

[60]  D. Pandya,et al.  Fiber Pathways of the Brain , 2006 .

[61]  Vann Bennett,et al.  Membrane domains based on ankyrin and spectrin associated with cell-cell interactions. , 2009, Cold Spring Harbor perspectives in biology.

[62]  Mark E. Bastin,et al.  White Matter Tractography in Bipolar Disorder and Schizophrenia , 2008, Biological Psychiatry.

[63]  C. Hoggart,et al.  Genome‐wide significance for dense SNP and resequencing data , 2008, Genetic epidemiology.

[64]  S. Strakowski,et al.  Functional MRI of Sustained Attention in Bipolar Mania , 2010, Molecular Psychiatry.

[65]  E. Leibenluft,et al.  Impaired probabilistic reversal learning in youths with mood and anxiety disorders , 2009, Psychological Medicine.

[66]  Peter N. C. Mohr,et al.  Neural Processing of Risk , 2010, The Journal of Neuroscience.

[67]  Torsten Rohlfing,et al.  Fiber tracking functionally distinct components of the internal capsule , 2010, Neuropsychologia.

[68]  W. Drevets,et al.  Toward Constructing an Endophenotype Strategy for Bipolar Disorders , 2006, Biological Psychiatry.

[69]  M. Phillips,et al.  A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder , 2008, Molecular Psychiatry.

[70]  C. Beaulieu,et al.  The basis of anisotropic water diffusion in the nervous system – a technical review , 2002, NMR in biomedicine.

[71]  G. Kindlmann,et al.  Orthogonal tensor invariants and the analysis of diffusion tensor magnetic resonance images , 2006, Magnetic resonance in medicine.

[72]  Muriel Walshe,et al.  White matter microstructural impairments and genetic liability to familial bipolar I disorder , 2009, British Journal of Psychiatry.

[73]  R. Fisher FREQUENCY DISTRIBUTION OF THE VALUES OF THE CORRELATION COEFFIENTS IN SAMPLES FROM AN INDEFINITELY LARGE POPU;ATION , 1915 .

[74]  K. Livingston,et al.  Anatomical bias of the limbic system concept. A proposed reorientation. , 1971, Archives of neurology.

[75]  Robert C. Thompson,et al.  Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry , 2009, Proceedings of the National Academy of Sciences.

[76]  S. Cichon,et al.  Neural Mechanisms of a Genome-Wide Supported Psychosis Variant , 2009, Science.

[77]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.