Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure

McIntosh, Andrew M.; Job, Dominic; Moorhead, William J.; Harrison, Lesley K.; Whalley, Heather C.; Johnstone, Eve C.; Lawrie, Stephen M.

doi:10.1002/ajmg.b.30254

Cited by 113 publications

(86 citation statements)

References 47 publications

(59 reference statements)

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“…McDonald et al (2004) reported a negative association between genetic risk for BD and gray matter volume in the right medial frontal gyrus, anterior cingulate gyrus, and striatum. However, McIntosh et al (2006) did not find any effect of genetic liability in relatives from families multiply affected with BD. Both research groups conducted further analyses on their samples.…”

Section: Introductionmentioning

confidence: 63%

Dissociable Brain Structural Changes Associated with Predisposition, Resilience, and Disease Expression in Bipolar Disorder

Kempton¹,

Haldane²,

Jogia³

et al. 2009

J. Neurosci.

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Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their firstdegree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states.

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Section: Introductionmentioning

confidence: 63%

Dissociable Brain Structural Changes Associated with Predisposition, Resilience, and Disease Expression in Bipolar Disorder

Kempton¹,

Haldane²,

Jogia³

et al. 2009

J. Neurosci.

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“…2 These findings have been associated with increased genetic liability to psychosis, albeit to unidentified loci 4 and by functional imaging studies in patients with schizophrenia 27,28 and those at high risk for genetic reasons. 29 These studies further implicate white matter disconnectivity in psychosis, although they cannot determine whether this is because of reduced axonal number, increased axonal disorganization or dysmyelination.…”

Section: Discussionmentioning

confidence: 95%

“…Using T 1 -weighted MRI, and DTI, abnormalities of white matter density and integrity have been shown in the ALIC in schizophrenia, 2,3 bipolar disorder 2,26 and their unaffected relatives. 2 These findings have been associated with increased genetic liability to psychosis, albeit to unidentified loci 4 and by functional imaging studies in patients with schizophrenia 27,28 and those at high risk for genetic reasons.…”

Section: Discussionmentioning

confidence: 99%

“…Subjects with the TT genotype also had significantly reduced white matter density as assessed by voxelbased morphometry compared to the C allele carriers at the tip of the right anterior capsule (peak 1: MNI coordinates = (29, 30, 7), t = 4.41, P-corrected = 0.028; peak 2: MNI coordinates = (29,26,8), t = 4.38, Pcorrected = 0.016; peak 3: MNI coordinates = (29,23,12), t = 4.26, P-corrected = 0.023). The associated cluster extended both medially and laterally into frontal white matter (Figure 1).…”

Section: T 1 -Weighted Imagingmentioning

confidence: 99%

“…2,3 These abnormalities are shared by unaffected relatives in proportion to their proximity to an affected subject. 4 These findings suggest that white matter density reductions are likely to be associated with shared genetic factors, although no specific genetic variants have yet been found which account for these findings.…”

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

The effects of a neuregulin 1 variant on white matter density and integrity

et al. 2007

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Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T 1 -weighted MRI) and integrity (DTI) was ascertained. Subjects with the riskassociated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

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Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability

Goldman¹,

Pezawas²,

Mattay³

et al. 2009

Arch Gen Psychiatry

236

165

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Context Schizophrenia is a brain disorder with predominantly genetic risk factors, and previous research has identified heritable cortical and subcortical reductions in local brain volume. To our knowledge, cortical thickness, a measure of particular interest in schizophrenia, has not previously been evaluated in terms of its heritability in relationship to risk for schizophrenia. Objective To quantify the distribution and heritability of cortical thickness changes in schizophrenia. Design We analyzed a large sample of normal controls, affected patients, and unaffected siblings using a surface-based approach. Cortical thickness was compared between diagnosis groups on a surfacewide node-by-node basis. Heritability related to disease risk was assessed in regions derived from an automated cortical parcellation algorithm by calculating the Risch λ. Setting Research hospital. Participants One hundred ninety-six normal controls, 115 affected patients with schizophrenia, and 192 unaffected siblings. Main Outcome Measure Regional cortical thickness. Results Node-by-node mapping statistics revealed widespread thickness reductions in the patient group, most pronouncedly in the frontal lobe and temporal cortex. Unaffected siblings did not significantly differ from normal controls at the chosen conservative threshold. Risch λ analysis revealed widespread evidence for heritability for cortical thickness reductions throughout the brain. Conclusions To our knowledge, the present study provides the first evidence of broadly distributed and heritable reductions of cortical thickness alterations in schizophrenia. However, since only trend-level reductions of thickness were observed in siblings, cortical thickness per se (at least as measured by this approach) is not a strong intermediate phenotype for schizophrenia.

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Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure

Cited by 113 publications

References 47 publications

Dissociable Brain Structural Changes Associated with Predisposition, Resilience, and Disease Expression in Bipolar Disorder

Dissociable Brain Structural Changes Associated with Predisposition, Resilience, and Disease Expression in Bipolar Disorder

The effects of a neuregulin 1 variant on white matter density and integrity

Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability

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