Association of Genetic Risks for Schizophrenia and Bipolar DisorderWith Specific and Generic Brain Structural Endophenotypes

McDonald, Colm; Bullmore, Edward T.; Sham, Pak C.; Chitnis, Xavier; Wickham, Harvey; Bramon, Elvira; Murray, Robin M.

doi:10.1001/archpsyc.61.10.974

Cited by 365 publications

(324 citation statements)

References 58 publications

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“…Strong support for this hypothesis comes from another study in which genetic risk for both schizophrenia and BD in patients and their first-degree relatives was associated with distributed white matter volume deficits that were anatomically coincident in the left prefrontal and temporoparietal regions. 245 Specific for BD were changes in the anterior corpus callosum and right frontal and right parietal regions white matter present both in bipolar patients and their first-degree relatives. 245 Significantly smaller bilateral white matter volume within superior temporal gyrus was found also in mostly euthymic bipolar children and adolescents.…”

Section: Basal Gangliamentioning

confidence: 98%

“…245 Specific for BD were changes in the anterior corpus callosum and right frontal and right parietal regions white matter present both in bipolar patients and their first-degree relatives. 245 Significantly smaller bilateral white matter volume within superior temporal gyrus was found also in mostly euthymic bipolar children and adolescents. 246 First-episode manic patients exhibited a trend towards reduced total cerebral white matter and significantly larger ratios of grey and white matter relative to healthy controls.…”

Section: Basal Gangliamentioning

confidence: 98%

“…212 Other studies, including a meta-analysis of available data, reported no change in total or prefrontal white matter, however. [193][194][195][247][248][249] Anterior cingulate In a recent study of patients with BD, schizophrenia, and their first-degree relatives, McDonald et al 245 examined associations between genetic liability and variations in grey or white matter volumes. Genetic risk for BD was specifically related to grey matter deficits in the right anterior cingulate gyrus and ventral striatum.…”

Section: Basal Gangliamentioning

confidence: 99%

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The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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Section: Basal Gangliamentioning

confidence: 98%

Section: Basal Gangliamentioning

confidence: 98%

Section: Basal Gangliamentioning

confidence: 99%

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The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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“…Um endofenótipo pode ser um traço neurofisiológico, neuropsicológico, cognitivo, neuroanatômico bioquímico ou endocrinológico herdado. Como resultado dessa abordagem há recentes evidências mostrando que o risco genético para TB está associado à deficiência volumétrica da substância cinzenta no giro cingulado anterior direito e no estriado ventral (McDonald et al, 2004) e à deficiência no tempo de reação e amplitude de potencial evocado P300 (Pierson et al, 2000). Associação de variantes gênicas com traços de personalidade, como impulsividade, com idade de início da doença e com resposta medicamentosa também se mostra promissora no entendimento da herdabilidade do TB.…”

Section: Discussionunclassified

“…McMahon et al (1995) observaram que pacientes bipolares possuem com maior freqüência mães afetadas do que pais afetados e mais ancestrais maternos afetados que ancestrais paternos, o que sugere aumento do risco para prole de mães afetadas. Alguns aspectos de herança genética podem determinar esse padrão.…”

Section: Imprintingunclassified

Fatores genéticos e ambientais na manifestação do transtorno bipolar

Michelon¹,

Vallada²

2005

Rev. psiquiatr. clín.

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ResumoO transtorno bipolar (TB) possui alta prevalência na população mundial e causa perdas significativas na vida dos portadores. É uma doença com importante fator genético, cuja herança se caracteriza por mecanismos complexos de transmissão envolvendo múltiplos genes que estão sob influência de inúmeros fatores ambientais. Várias estratégias de investigação genética têm sido utilizadas para identificar genes determinantes de vulnerabilidade ao TB. Estudos com gêmeos, de ligação e de associação permitiram caracterizar a herdabilidade dessa doença, identificar regiões cromossômicas potencialmente associadas ao TB e avaliar a contribuição de genes candidatos na sua etiologia. Em virtude da complexidade do modo de transmissão do TB e de sua heterogeneidade fenotípica muitas dificuldades são encontradas na identificação desses genes. Paralelamente, estudos psicossociais apontam para fatores ambientais de relevância no desencadeamento do TB. Com a compreensão crescente dos mecanismos epigenéticos de controle da expressão gênica, incluindo a interação do genoma com fatores ambientais, e a abordagem dimensional dos transtornos mentais, abrem-se perspectivas promissoras de pesquisas futuras para elucidar os fatores envolvidos na manifestação do transtorno bipolar.Palavras-chave: Transtorno bipolar, genética psiquiátrica, fatores ambientais, aconselhamento genético.

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