Effects of a<i>CACNA1C</i>genotype on attention networks in healthy individuals

Thimm, Markus; Kircher, Tilo; Kellermann, Thilo; Markov, Valentin; Krach, Sören; Jansen, Andreas; Zerres, Klaus; Eggermann, Thomas; Stöcker, Tony; Shah, N. Jon; Nöthen, Markus M.; Rietschel, Marcella; Witt, Stephanie H.; Mathiak, Klaus; Krug, Axel

doi:10.1017/s0033291710002217

Cited by 90 publications

(45 citation statements)

References 92 publications

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“…Using the fMRI method, Bigos et al (2010) and Krug et al (2010) found that the risk allele was associated with increased activity of the DLPFCFan indication of poorer working memory. Studying mostly the same subjects as those of Krug et al's (2010) study, Thimm et al (2011) found that, compared with other genotypes, the rs1006737 risk allele homozygotes showed Figure 1 Working memory by rs1006737 genotype and diagnosis. For SCZ patients and healthy controls, compared with the major allele (G) homozygotes, clinical risk allele (A) carriers made more errors at both the 1-back task (the panel a) and the BX condition of the DPX task (the panel b) and showed higher BX-AY difference scores (the panel c).…”

Section: Discussionmentioning

confidence: 92%

The Effects of CACNA1C Gene Polymorphism on Spatial Working Memory in Both Healthy Controls and Patients with Schizophrenia or Bipolar Disorder

Zhang

Shen

et al. 2011

Neuropsychopharmacol

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Section: Discussionmentioning

confidence: 92%

The Effects of CACNA1C Gene Polymorphism on Spatial Working Memory in Both Healthy Controls and Patients with Schizophrenia or Bipolar Disorder

Zhang

Shen

et al. 2011

Neuropsychopharmacol

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“…This information is required for understanding the pathway by which genetic risk for depression results in disease. The expanding literature on examining the association between intermediate phenotypes and markers found to be genome-wide significant for a psychiatric disease [80][81][82][83][84][85][86] is testament to the perceived value of intermediate phenotypes in interpreting genetic signals.…”

Section: Discussionmentioning

confidence: 99%

Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease

Flint

Timpson

Munafò

2014

Trends in Neurosciences

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Intermediate phenotypes are traits positioned somewhere between genetic variation and disease. They represent a target for attempts to find disease-associated genetic variants and elucidation of mechanisms. Psychiatry has been particularly enamored with intermediate phenotypes, due to uncertainty about disease etiology, inconclusive results in early psychiatric genetic studies, and their appeal relative to traditional diagnostic categories. Here, we argue that new genetic findings are relevant to the question of the utility of these constructs. In particular, results from genomewide association studies of psychiatric disorders now allow an assessment of the potential role of particular intermediate phenotypes. Based on such an analysis, as well as other recent results, we conclude that intermediate phenotypes are likely to be most valuable in understanding mechanism. What's the use of an endophenotype?Until recently, genetic approaches in psychiatric disease had enjoyed limited success, but large-scale collaborative a genome-wide association studies (GWAS) have now begun to identify common and rare variants associated with schizophrenia, bipolar disorder and autism spectrum disorders [1][2][3][4][5][6][7][8][9][10][11]. An alternative to these agnostic, large-scale approaches is to focus instead on phenotypes thought to reflect disease processes. In this review we refer to these phenotypes as intermediate phenotypes, rather than endophenotypes. Definitions of 'endophenotype' grace every review of this area (see Box 1 for some examples), and they are not all alike. For our purposes, the critical distinction is between definitions in which an endophenotype is considered to lie on the causal pathway to disease, and those in which it is more generally an index of the likelihood that a subject has the disease (and could serve as a biomarker). This distinction, noted by Walters and Owen [12], has been treated in detail by Kendler and Neale [13]. Here we distinguish two ways in which intermediate phenotypes could be used in genetic studies, and review their utility in genetic analysis of psychiatric disease.Correspondence to Jonathan Flint: jf@well.ox.ac.uk. The first use of intermediate phenotypes is to aid gene discovery. For example, if a genetic study of major depression fails to identify a signal, then researchers may decide to focus their attention on cognitive variables instead, reasoning that individual differences in the processing of stimuli representing negative affect (such as a bias in the interpretation of sad or happy faces [14]) might be an important mechanistic pathway, better reflecting the underlying biology, and therefore more genetically tractable. In addition, they might include data indicating activity in brain areas involved in processing affective or motivational stimuli (such as the amygdala and nucleus accumbens). With results in hand, researchers can combine the additional phenotypes with the diagnostic information, searching for a subgroup in their data in which the genetic signal i...

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“…Most prominently, The intronic polymorphism rs4765914 in CACNA1C has been previously associated independently with bipolar disorder [173,174], schizophrenia [19] and major depressive disorder [175]. Genetic imaging approaches linked CACNA1C variants along an endophenotypic spectrum similar to that observed for TCF4 including attention deficits [176] and memory formation [177]. Of note, the C-terminus of CACNA1C encodes a transcription factor that is implicated in activity-transcription coupling by regulated proteolysis at the membrane [178].…”

Section: +mentioning

confidence: 99%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms. AbstractSchizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits.Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4 behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental and possibly also plasticity related transcriptional programs in the CNS and changes of TCF4 expression appear to affect brain networks important for information processing.Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis to identify the und...

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Effects of aCACNA1Cgenotype on attention networks in healthy individuals

Abstract: Our results suggest that CACNA1C plays a role in the development of specific attention deficits in psychiatric disorders by modulation of neural attention networks.

Cited by 90 publications

References 92 publications

The Effects of CACNA1C Gene Polymorphism on Spatial Working Memory in Both Healthy Controls and Patients with Schizophrenia or Bipolar Disorder

The Effects of CACNA1C Gene Polymorphism on Spatial Working Memory in Both Healthy Controls and Patients with Schizophrenia or Bipolar Disorder

Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

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