Association of TMEM132D, COMT, and GABRA6 genotypes with cingulate, frontal cortex and hippocampal emotional processing in panic and major depressive disorder

Inoue, Ayako; Akiyoshi, Jotaro; Muronaga, Masaaki; Masuda, Koji; Aizawa, Saeko; Ishitobi, Yoshinobu; Higuma, Haruka; Maruyama, Yoshihiro; Ninomiya, Taiga; Tanaka, Yoshihiro; Hanada, Hiroaki; Kawano, Yoshihisa

doi:10.3109/13651501.2015.1043133

Cited by 22 publications

(20 citation statements)

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“…Previous research points to the possible involvement of GABA in the propensity of anxious and fearful traits and temperaments via its GABA-A receptor-mediated inhibitory effects with even minor genetic variation possibly contributing to an alteration in anxiety-related traits and individual differences in threat-related responses 26 , 27 . Specifically, GABRA6 TT carriers were shown to exhibit increased harm avoidance and anticipatory worry 26 , 28 , and T carrier panic disorder patients showed increased reaction to fearful faces in an fMRI study 24 thus suggesting an association between GABRA6 and different aspects of anxiety 14 , 24 , 25 .…”

Section: Discussionmentioning

confidence: 94%

“…Previous results suggested an association between hormonal and psychological stress response and the GABRA6 gene. Variations in GABRA6 and specifically rs3219151 T allele was found to be related to higher baseline salivary cortisol levels 13 and higher ACTH, cortisol and blood pressure increase upon stress exposure in several studies 14 , 24 , 25 . These results suggest that decreased inhibition of the HPA axis due to GABA deficits may contribute to increased hormonal and physiological stress response 14 which is well-known to be associated with risks of developing mental health problems including depression and suicide.…”

Section: Discussionmentioning

confidence: 95%

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A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene

Gonda

Sarginson

Eszlári

et al. 2017

Sci Rep

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Low GABA transmission has been reported in suicide, and GABRA6 rs3219151 T allele has been associated with greater physiological and endocrine stress response in previous studies. Although environmental stress also plays a role in suicide, the possible role of this allele has not been investigated in this respect. In our present study effect of rs3219151 of GABRA6 gene in interaction with recent negative life events on lifetime and current depression, current anxiety, as well as lifetime suicide were investigated using regression models in a white European general sample of 2283 subjects. Post hoc measures for phenotypes related to suicide risk were also tested for association with rs3219151 in interaction with environmental stress. No main effect of the GABRA6 rs3219151 was detected, but in those exposed to recent negative life events GABRA6 T allele increased current anxiety and depression as well as specific elements of suicide risk including suicidal and death-related thoughts, hopelessness, restlessness and agitation, insomnia and impulsiveness as measured by the STOP task. Our data indicate that stress-associated suicide risk is elevated in carriers of the GABRA6 rs3219151 T allele with several independent markers and predictors of suicidal behaviours converging to this increased risk.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 95%

A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene

Gonda

Sarginson

Eszlári

et al. 2017

Sci Rep

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“…Fig 7D). Notably, Gabra6, among the most highly dysregulated genes in Pclo KO rats, was also not detectable in the hypothalamus and cortex samples of the MDD rat model (Fig 7E), connecting Gabra6 with both Pclo and MDD phenotypes [20,45].…”

Section: Recessive Pclo Traits Are Mappable To Allelic Markers For Mamentioning

confidence: 96%

“…By analogy, the pre-copulatory mating behavior and aggression phenotypes reported here in Pclo SBΔ4-25 rats demonstrate Piccolo's potential control over sensory responses to social cues. Importantly, while both Piccolo and Gabra6 variants are associated with MDD and altered emotional processing based on studies in humans [20,45], no direct sexual connection to either gene has been reported in humans. The functional significance of the tight control of Gabra6 expression by Pclo has yet to be investigated, but one possibility is that a loss of synaptic integrity leads to Gabra6 down-regulation [58].…”

Section: Affective Disorder and Limbic System Neurotransmission Phenomentioning

confidence: 99%

Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

Medrano

Singh

Plautz

et al. 2018

Preprint

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Successful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Atg13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive.Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction. Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact one's emotions, including depression and bipolar disorder.Although studies in human populations implicate changes to Piccolo's DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutationdependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.pathologies, and in males, Atg13 gt/gt was further complicated with abnormal spermatozoa. Thus, the cause of infertility of Atg13 gt/gt rats is a cumulation of general fitness problems. Compromised neurotransmission in Pclo mutantsDespite their reproductive failure (Fig 2A), Pclo gt/gt mutant rats did not display any obvious dysfunction during gametogenesis (S2A and S2C Fig). Numbers of epididymal spermatozoa from Pclo gt/gt rats were relatively normal (Fig 2C). However, spermatozoa from Pclo gt/gt rats were not found in vaginal swabs of WT females (6 of 6 breeder pairs) (Fig 4A, and spermatozoa from WT males were not detected in Pclo gt/gt females (6 of 6 breeder pairs) (Fig 4A), suggesting that the mating did not actuall...

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“…Symptom severity scores in the COMT AA/AG genotype group were positively correlated with the FA in WM tracts. Inoue et al[118] investigated possible associations of COMT, human TransMEMbrane protein 132D (TMEM132D), and GABA receptor alpha 6 subunit (GABRA6) genotypes in PD patients and healthy controls. The polymorphisms rs4680 in COMT and rs3219151 in GABRA6 showed positive associations with PD.…”

Section: Resultsmentioning

confidence: 99%

Functional neuroanatomy in panic disorder: Status quo of the research

Sobanski¹,

Wagner²

2017

WJP

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AIMTo provide an overview of the current research in the functional neuroanatomy of panic disorder.METHODSPanic disorder (PD) is a frequent psychiatric disease. Gorman et al (1989; 2000) proposed a comprehensive neuroanatomical model of PD, which suggested that fear- and anxiety-related responses are mediated by a so-called “fear network” which is centered in the amygdala and includes the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus coeruleus and other brainstem sites. We performed a systematic search by the electronic database PubMed. Thereby, the main focus was laid on recent neurofunctional, neurostructural, and neurochemical studies (from the period between January 2012 and April 2016). Within this frame, special attention was given to the emerging field of imaging genetics.RESULTSWe noted that many neuroimaging studies have reinforced the role of the “fear network” regions in the pathophysiology of panic disorder. However, recent functional studies suggest abnormal activation mainly in an extended fear network comprising brainstem, anterior and midcingulate cortex (ACC and MCC), insula, and lateral as well as medial parts of the prefrontal cortex. Interestingly, differences in the amygdala activation were not as consistently reported as one would predict from the hypothesis of Gorman et al (2000). Indeed, amygdala hyperactivation seems to strongly depend on stimuli and experimental paradigms, sample heterogeneity and size, as well as on limitations of neuroimaging techniques. Advanced neurochemical studies have substantiated the major role of serotonergic, noradrenergic and glutamatergic neurotransmission in the pathophysiology of PD. However, alterations of GABAergic function in PD are still a matter of debate and also their specificity remains questionable. A promising new research approach is “imaging genetics”. Imaging genetic studies are designed to evaluate the impact of genetic variations (polymorphisms) on cerebral function in regions critical for PD. Most recently, imaging genetic studies have not only confirmed the importance of serotonergic and noradrenergic transmission in the etiology of PD but also indicated the significance of neuropeptide S receptor, CRH receptor, human TransMEMbrane protein (TMEM123D), and amiloride-sensitive cation channel 2 (ACCN2) genes.CONCLUSIONIn light of these findings it is conceivable that in the near future this research will lead to the development of clinically useful tools like predictive biomarkers or novel treatment options.

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Association of TMEM132D, COMT, and GABRA6 genotypes with cingulate, frontal cortex and hippocampal emotional processing in panic and major depressive disorder

Abstract: These results suggest that TMEM132D, GABRA6, and COMT variants may increase vulnerability to panic.

Cited by 22 publications

References 91 publications

A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene

A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene

Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

Functional neuroanatomy in panic disorder: Status quo of the research

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