The CACNA1C risk variant for bipolar disorder influences limbic activity

Wessa, Michèle; Linke, Julia; Witt, Stephanie H.; Nieratschker, Vanessa; Esslinger, Christine; Kirsch, Peter; Grimm, O.; Hennerici, Michael G.; Gass, Achim; King, Andrea; Rietschel, Marcella

doi:10.1038/mp.2009.103

Cited by 80 publications

(74 citation statements)

References 10 publications

(11 reference statements)

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“…This idea is further supported by another study that showed increased amygdala activation in response to reward in carriers of the risk allele of CACNA1C rs1006737, a genome-wide supported risk variant for bipolar disorder [208].…”

Section: Motivationsupporting

confidence: 66%

Emotional and Motivational Processes in Bipolar Disorder: A Neural Network Perspective

Wessa¹,

Linke²

2013

Psychiatric Disorders - New Frontiers in Affective Disorders

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Section: Motivationsupporting

confidence: 66%

Emotional and Motivational Processes in Bipolar Disorder: A Neural Network Perspective

Wessa¹,

Linke²

2013

Psychiatric Disorders - New Frontiers in Affective Disorders

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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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“…The effect may be exerted by the rs2339104 genotype but only in the presence of the rs1034936 T allele. The effects of this particular gene have been validated in multiple different ways [39,40,41,42,43]. Variants within CACNA1C, which encodes for a subunit forming a calcium channel, may increase intracellular calcium at neuronal levels.…”

Section: Discussionmentioning

confidence: 99%

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Calabrò¹,

Mandelli²,

Crisafulli³

et al. 2016

Neuropsychobiology

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Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

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The CACNA1C risk variant for bipolar disorder influences limbic activity

Cited by 80 publications

References 10 publications

Emotional and Motivational Processes in Bipolar Disorder: A Neural Network Perspective

Emotional and Motivational Processes in Bipolar Disorder: A Neural Network Perspective

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

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

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