Validation of candidate anxiety disorder genes using a carbon dioxide challenge task

Savage, Jeanne E.; McMichael, Omari; Gorlin, Eugenia I.; Beadel, Jessica R.; Teachman, Bethany A.; Vladimirov, Vladimir I.; Hettema, John M.; Roberson‐Nay, Roxann

doi:10.1016/j.biopsycho.2015.04.006

Cited by 19 publications

(12 citation statements)

References 59 publications

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“…Two murine studies, however, have implicated a role of the serotonin system in sensitivity to CO 2 [Li and Nattie, ; Puissant et al, ]. In another human study, SNPs from multiple candidate genes previously implicated in ADs/traits ( CCKBR , SLC6A4 , GAD1 , COMT , BDNF , TMEM132D , ASIC1 , ASIC2 , ADCYAP1R1 , and FKBP5 ) were evaluated with respect to respiratory response to a sustained carbon dioxide challenge task [Savage et al, ]. Of these, only the ASIC1 gene was significantly associated with basal respiratory rate and none with respiratory response to the task.…”

Section: Resultsmentioning

confidence: 99%

The genetics of anxiety‐related negative valence system traits

Savage

Sawyers

Roberson‐Nay

et al. 2016

American J of Med Genetics Pt B

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NIMH’s Research Domain Criteria (RDoC) domain of negative valence systems (NVS) captures constructs of negative affect such as fear and distress traditionally subsumed under the various internalizing disorders. Through its aims to capture dimensional measures that cut across diagnostic categories and are linked to underlying neurobiological systems, a large number of phenotypic constructs have been proposed as potential research targets. Since “genes” represent a central “unit of analysis” in the RDoC matrix, it is important for studies going forward to apply what is known about the genetics of these phenotypes as well as fill in the gaps of existing knowledge. This article reviews the extant genetic epidemiological data (twin studies, heritability) and molecular genetic association findings for a broad range of putative NVS phenotypic measures. We find that scant genetic epidemiological data is available for experimentally-derived measures such as attentional bias, peripheral physiology, or brain-based measures of threat response. The molecular genetic basis of NVS phenotypes is in its infancy, since most studies have focused on a small number of candidate genes selected for putative association to anxiety disorders (ADs). Thus, more research is required to provide a firm understanding of the genetic aspects of anxiety-related NVS constructs.

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Section: Resultsmentioning

confidence: 99%

The genetics of anxiety‐related negative valence system traits

Savage

Sawyers

Roberson‐Nay

et al. 2016

American J of Med Genetics Pt B

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“…In healthy volunteers, PD-associated alleles were also associated with amygdala volume and amygdala reactivity to emotional faces . In a subsequent report, an intronic ACCN2 SNP was associated with respiratory rate and anxiety sensitivity (but not panic symptoms) in response to inhalation of CO 2 -enriched air among healthy volunteers (Savage et al, 2015).…”

Section: Common Genetic Variationmentioning

confidence: 99%

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Smoller

2015

Neuropsychopharmacol

378

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Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders-for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene-environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research.

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“…CO 2 hypersensitivity, as indexed by exaggerated emotional and respiratory responses to CO 2 -enriched air mixture, is a useful investigational tool for identifying individuals at risk for later pathophysiology. Studies have used the CO 2 challenge task for the validation of candidate genes for panic disorder (Savage et al, 2015), and treatment efficacy in panic patients (Perna et al, 2002). Recent work has established the CO 2 inhalation paradigm as a translational cross-species model for panic (Leibold et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats

et al. 2017

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Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2 positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal grey (VLPAG) subdivision in CO2-sensitive strains. Conversely, DβH positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.

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Validation of candidate anxiety disorder genes using a carbon dioxide challenge task

Cited by 19 publications

References 59 publications

The genetics of anxiety‐related negative valence system traits

The genetics of anxiety‐related negative valence system traits

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats

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