FKBP5 and Attention Bias for Threat

Fani, Negar; Gutman, David; Tone, Erin B.; Almli, Lynn M.; Mercer, Kristina B.; Davis, Jennifer S.; Glover, Ebony M.; Jovanović, Tanja; Bradley, Bekh; Dinov, Ivo D.; Zamanyan, Alen; Toga, Arthur W.; Binder, Elisabeth B.; Ressler, Kerry J.

doi:10.1001/2013.jamapsychiatry.210

Cited by 120 publications

(66 citation statements)

References 69 publications

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“…Two ROI-based studies indicate that heightened activation in the amygdala (White et al, 2012) and hippocampus (Fani et al, 2013) to threat cues in carriers of risk alleles for various FKBP5 polymorphisms identified in previous studies (Binder et al, 2008). White et al (2012) found these effects to be attributable to a gene by environment interaction; Fani et al (2013) did not observe interactive effects, but found that, compared to individuals without the risk allele, FKBP5 risk allele carriers (for SNP rs1360780) demonstrated an attentional bias toward threat cues and corresponding increases in hippocampal activation. Heightened amygdala responses to threat cues (angry and fearful faces) have also been observed in risk allele carriers for COMT (specifically, Val-allele carriers for SNP rs4680) (Domschke et al, 2012) and NPY (Domschke et al, 2010b).…”

Section: Neuroimaging Geneticsmentioning

confidence: 89%

Genetic approaches to understanding post-traumatic stress disorder

Almli¹,

Fani²,

Smith³

et al. 2013

Int. J. Neuropsychopharm.

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103

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Post-traumatic stress disorder (PTSD) is increasingly recognized as both a disorder of enormous mental health and societal burden, but also as an anxiety disorder that may be particularly understandable from a scientific perspective. Specifically, PTSD can be conceptualized as a disorder of fear and stress dysregulation, and the neural circuitry underlying these pathways in both animals and humans are becoming increasingly well understood. Furthermore, PTSD is the only disorder in psychiatry in which the initiating factor, the trauma exposure, can be identified. Thus, the pathophysiology of the fear and stress response underlying PTSD can be examined and potentially interrupted. Twin studies have shown that the development of PTSD following a trauma is heritable, and that genetic risk factors may account for up to 30–40% of this heritability. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review will examine gene pathways that have recently been analysed, primarily through candidate gene studies (including neuroimaging studies of candidate genes), in addition to genome-wide associations and the epigenetic regulation of PTSD. Future and on-going studies are utilizing larger and collaborative cohorts to identify novel gene candidates through genome-wide association and other powerful genomic approaches. Identification of PTSD biological pathways strengthens the hope of progress in the mechanistic understanding of a model psychiatric disorder and allows for the development of targeted treatments and interventions.

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Section: Neuroimaging Geneticsmentioning

confidence: 89%

Genetic approaches to understanding post-traumatic stress disorder

Almli¹,

Fani²,

Smith³

et al. 2013

Int. J. Neuropsychopharm.

Self Cite

103

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Section: Introductionmentioning

confidence: 99%

“…Of note, the activity of the FK506 binding protein 5 (FKBP5) gene has been found associated with several depression risk factors and hippocampal features (Binder et al 2008;Fani et al 2013;Klengel et al 2013). The rs1360780 variantone of the most studied single nucleotide polymorphisms (SNPs) in the FKBP5 gene-has been linked to hippocampal volume and function in depression and stress (Fani et al 2013;Pagliaccio et al 2014;Fani et al 2014). Though this may be related to genetic factors underlying a communicational deficit of the hippocampus with other brain areas in individuals with depressive psychopathology, to the best of our knowledge, no previous report has evaluated the (putative) association between this SNP and the organization of white matter tracts connecting the hippocampus to the rest of the brain.…”

Section: Introductionmentioning

confidence: 99%

FKBP5 modulates the hippocampal connectivity deficits in depression: a study in twins

Córdova‐Palomera

Reus

Fatjó‐Vilas

et al. 2016

Brain Imaging and Behavior

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The hippocampus is a key modulator of stress responses underlying depressive behavior. While FKBP5 has been found associated with a large number of stress-related outcomes and hippocampal features, its potential role in modifying the hippocampal communication transfer mechanisms with other brain regions remains largely unexplored. The putative genetic or environmental roots of the association between depression and structural connectivity alterations of the hippocampus were evaluated combining diffusion weighted imaging with both a quantitative genetics approach and molecular information on the rs1360780 single nucleotide polymorphism, in a sample of 54 informative monozygotic twins (27 pairs). Three main results were derived from the present analyses. First, graph-theoretical measures of hippocampal connectivity were altered in depression. Specifically, decreased connectivity strength and increased network centrality of the right hippocampus were found in depressed individuals. Second, these hippocampal alterations are potentially driven by familial factors (genes plus shared environment). Third, there is an additive interaction effect between FKBP5's rs1360780 variant and the graph-theoretical metrics of hippocampal connectivity to influence depression risk. Our data reveals alterations of the communication patterns between the hippocampus and the rest of the brain in depression, effects potentially driven by overall familial factors (genes plus shared twin environment) and modified by the FKBP5 gene.

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“…First, the changes in GR sensitivity during the feedback regulation of the HPA axis lead to prolonged stress-related cortisol release in individuals carrying the variant that is associated with higher FKBP5 mRNA induction (Buchmann et al, 2014; Ising et al, 2008; Luijk et al, 2010). Second, the high induction allele is associated with different behavioural responses to threat and trauma such as increased dissociation following trauma, increased bias towards threat and increased intrusions (Cheung & Bryant, 2015; Fani et al, 2013; Koenen et al, 2005). Third, this variant is also associated with both structural as well as functional changes in brain imaging with increased hippocampal and amygdala activity to threat and white matter abnormalities in the posterior cingulum in high expression allele carriers (Fani et al, 2013, 2014, 2016; Hirakawa et al, 2016; Holz et al, 2015).…”

mentioning

confidence: 99%

“…Second, the high induction allele is associated with different behavioural responses to threat and trauma such as increased dissociation following trauma, increased bias towards threat and increased intrusions (Cheung & Bryant, 2015; Fani et al, 2013; Koenen et al, 2005). Third, this variant is also associated with both structural as well as functional changes in brain imaging with increased hippocampal and amygdala activity to threat and white matter abnormalities in the posterior cingulum in high expression allele carriers (Fani et al, 2013, 2014, 2016; Hirakawa et al, 2016; Holz et al, 2015). Overall, these human genetic studies thus agree that high FKBP5 expression is associated with a similar phenotype profile as described in animal studies, including an increased bias towards threat, increased intrusions and delayed normalization of the stress response following psychosocial stressors.…”

mentioning

confidence: 99%

Dissecting the molecular mechanisms of gene x environment interactions: implications for diagnosis and treatment of stress-related psychiatric disorders

Binder

2017

European Journal of Psychotraumatology

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Epidemiological studies indicate a combined contribution of genetic and environmental factors, mainly exposure to adverse life events, in the risk for psychiatric disease. Understanding how adverse life events interact with genetic predisposition on the molecular level to shape risk and resilience to psychiatric disorders may yield important insight into disease mechanism. Using the example of the molecular mechanisms of interaction of functional genetic variants within the stress-regulating gene FKBP5 and early adversity, it is delineated how this interaction could contribute to transdiagnostic disease risk via a combined genetic and epigenetic disinhibition of FKBP5 transcription. This knowledge may now allow to develop biomarkers for a transdiagnostic subset of psychiatric patients and to personalize treatment.

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FKBP5 and Attention Bias for Threat

Cited by 120 publications

References 69 publications

Genetic approaches to understanding post-traumatic stress disorder

Genetic approaches to understanding post-traumatic stress disorder

FKBP5 modulates the hippocampal connectivity deficits in depression: a study in twins

Dissecting the molecular mechanisms of gene x environment interactions: implications for diagnosis and treatment of stress-related psychiatric disorders

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