New insights into the endophenotypic status of cognition in bipolar disorder: Genetic modelling study of twins and siblings

Georgiades, Anna; Rijsdijk, Frühling; Kane, Fergus; Rebollo‐Mesa, Irene; Kalidindi, Sridevi; Schulze, Katja; Ståhl, Daniel; Walshe, Muriel; Sahakian, Barbara J.; McDonald, Colm; Hall, Mei‐Hua; Murray, Robin M.; Kravariti, Eugenia

doi:10.1192/bjp.bp.115.167239

Cited by 13 publications

(12 citation statements)

References 45 publications

(68 reference statements)

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“…Our finding of enhanced performance may be attributable to the non-clinical sources of our sample and the euthymic state of the majority of probands and relatives. The significant familial association for visuospatial ability confirms the recent finding of substantial heritability of visuospatial learning in a twin-family study of a clinical sample of BPD (Georgiades et al, 2016). This finding is also notable given that males tend to outperform females on the PLOT (Gur et al, 2012; Moore et al, 2016), yet the BP-I group still outperforms the controls even though they are only 28% male (versus 47% male in controls).…”

Section: Discussionsupporting

confidence: 85%

“…Previous studies have demonstrated poorer performance in line orientation and other tests of visuospatial processing between BPD patients and controls (Frantom et al, 2008; Georgiades et al, 2016; Torres et al, 2010). Our finding of enhanced performance may be attributable to the non-clinical sources of our sample and the euthymic state of the majority of probands and relatives.…”

Section: Discussionmentioning

confidence: 86%

“…Neurocognitive endophenotypes have also been examined in large samples of extended pedigrees of probands with BPD (Fears et al, 2014; Glahn et al, 2010; Pagani et al, 2016) or with MDD (Glahn et al, 2012). These studies have discriminated genetic and environmental components of cognitive factors and their association with BPD (Georgiades et al, 2016). Neurocognitive domains that have been shown to have substantial heritability in these studies include: processing speed, verbal working memory, long-term memory, and verbal fluency (Fears et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Most participants in studies of neurocognitive endophenotypes for mood disorder subgroups have been recruited in clinical settings that represent the most severe cases (Bora et al, 2009; Volkert et al, 2016), often during the acute phase of mood disorders that may be complicated by affective state and medication use (Burdick et al, 2014; de Brito Ferreira Fernandes et al, 2016; Georgiades et al, 2016; Glahn et al, 2010; Lee et al, 2014; Xu et al, 2012). Associations found in these studies differ by source of the samples, mood disorder subgroups (Godard et al, 2011), clinical characteristics including current state (Martinez-Aran et al, 2004), medication use, psychotic features, severity, consequences (Jaeger et al, 2006; Martinez-Aran et al, 2007; Ruggero et al, 2007) or precursors of the disorder (Pavuluri et al, 2006), as well as substantial differences in the measures and domains assessed (Porter et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Neurocognitive performance as an endophenotype for mood disorder subgroups

Merikangas

Cui

Calkins

et al. 2017

Journal of Affective Disorders

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Background There is growing evidence that neurocognitive function may be an endophenotype for mood disorders. The goal of this study is to examine the specificity and familiality of neurocognitive functioning across the full range of mood disorder subgroups, including Bipolar I (BP-I), Bipolar II (BP-II), Major Depressive Disorders (MDD), and controls in a community-based family study. Methods A total of 310 participants from 137 families with mood spectrum disorders (n=151) and controls (n=159) completed the University of Pennsylvania’s Computerized Neurocognitive Battery (CNB) that assessed the accuracy and speed of task performance across five domains. Mixed effects regression models tested association and familiality. Results Compared to those without mood disorders, participants with BP-I had increased accuracy in complex cognition, while participants with MDD were more accurate in emotion recognition. There was also a significant familial association for accuracy of complex cognition. Mood disorder subgroups did not differ in performance speed in any of the domains. Limitations The small number of BP-I cases, and family size limited statistical power of these analyses, and the cross-sectional assessment of neurocognitive function precluded our ability to determine whether performance precedes or post dates onset of disorder. Conclusions This is one of the few community-based family studies of potential neurocognitive endophenotypes that includes the full range of mood disorder subgroups. There were few differences in neurocognitive function except enhanced accuracy in specific domains among those with BP-I and MDD. The differential findings across specific mood disorder subgroups substantiate their heterogeneity in other biologic and endophenotypic domains.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neurocognitive performance as an endophenotype for mood disorder subgroups

Merikangas

Cui

Calkins

et al. 2017

Journal of Affective Disorders

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“…Using psychosis as a dimension in grouping the participants, a family study revealed a gradient of performance on the working and declarative memory, executive functions, and attention with the poorest being in probands (i.e., SCH-P, BD-P with psychosis), intermediate in FDR of the psychosis spectrum, and highest in the FDR of the nonpsychotic spectrum disorder, supporting the notion that cognitive function in BD and SCH defines a psychosis continuum [51]. Structural equation modeling of cognitive data from 331 twins/siblings showed that illness state and concordance for BD had a modest impact of verbal episodic memory and spatial working memory on the bipolar diathesis; IQ and visual-spatial learning, however, were associated with genetic diathesis to BD and with nonaffective symptomatology, also supporting the notion of psychosis continuum [52]. …”

Section: Resultsmentioning

confidence: 77%

Neurobiology of Risk for Bipolar Disorder

Özerdem

Ceylan

Can

2016

Curr Treat Options Psych

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Opinion statementBipolar disorder (BD) is a chronic mental illness which follows a relapsing and remitting course and requires lifetime treatment. The lack of biological markers for BD is a major difficulty in clinical practice. Exploring multiple endophenotypes to fit in multivariate genetic models for BD is an important element in the process of finding tools to facilitate early diagnosis, early intervention, prevention of new episodes, and follow-up of treatment response in BD. Reviewing of studies on neuroimaging, neurocognition, and biochemical parameters in populations with high genetic risk for the illness can yield an integrative perspective on the neurobiology of risk for BD. The most up-to-date data reveals consistent deficits in executive function, response inhibition, verbal memory/learning, verbal fluency, and processing speed in risk groups for BD. Functional magnetic resonance imaging (fMRI) studies report alterations in the activity of the inferior frontal gyrus, medial prefrontal cortex, and limbic areas, particularly in the amygdala in unaffected first-degree relatives (FDR) of BD compared to healthy controls. Risk groups for BD also present altered immune and neurochemical modulation. Despite inconsistencies, accumulating data reveals cognitive and imaging markers for risk and to a less extent resilience of BD. Findings on neural modulation markers are preliminary and require further studies. Although the knowledge on the neurobiology of risk for BD has been inadequate to provide benefits for clinical practice, further studies on structural and functional changes in the brain, neurocognitive functioning, and neurochemical modulation have a potential to reveal biomarkers for risk and resilience for BD. Multimodal, multicenter, population-based studies with large sample size allowing for homogeneous subgroup analyses will immensely contribute to the elucidation of biological markers for risk for BD in an integrative model.

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A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains

Ranlund

Calafato

Thygesen

et al. 2017

American J of Med Genetics Pt B

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This large multi‐center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi‐modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first‐degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event‐related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

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New insights into the endophenotypic status of cognition in bipolar disorder: Genetic modelling study of twins and siblings

Abstract: Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder.

Cited by 13 publications

References 45 publications

Neurocognitive performance as an endophenotype for mood disorder subgroups

Neurocognitive performance as an endophenotype for mood disorder subgroups

Neurobiology of Risk for Bipolar Disorder

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains

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