Abstract
In this review article, genetic variation associated with brain responses related
to acute and chronic stress reactivity and fear learning in humans is presented as
an important mechanism underlying posttraumatic stress disorder. We report that genes
related to the regulation of the hypothalamic-pituitary-adrenal axis, as well as genes
that modulate serotonergic, dopaminergic, and neuropeptidergic functions or plasticity,
play a role in this context. The strong overlap of the genetic targets involved in
stress and fear learning suggests that a dimensional and mechanistic model of the
development of posttraumatic stress disorder based on these constructs is promising.
Genome-wide genetic analyses on fear and stress mechanisms are scarce. So far, reliable
replication is still lacking for most of the molecular genetic findings, and the proportion
of explained variance is rather small. Further analysis of neurogenetic stress and
fear learning needs to integrate data from animal and human studies.
Keywords
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References
- Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women.Psychoneuroendocrinology. 2013; 38: 3029-3038
- A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus.Mol Psychiatry. 2013; 18: 937-942
- Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.Proc Natl Acad Sci U S A. 2013; 110: 8302-8307
- Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.Nature. 2011; 470: 492-497
- Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder.Biol Psychiatry. 2013; 74: 656-663
- Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks.Biol Psychiatry. 2009; 66: 708-711
- Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans.Transl Psychiatry. 2017; 7: e1169
- An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders.Transl Psychiatry. 2017; 7: e1158
- Research domain criteria (RDoC): Toward a new classification framework for research on mental disorders.Am J Psychiatry. 2010; 167: 748-751
- Learning and brain plasticity in mental disorders.Restor Neurol Neurosci. 2014; 32: 1-3
- Toward new approaches to psychotic disorders: The NIMH Research Domain Criteria project.Schizophr Bull. 2010; 36: 1061-1062
- Toward the future of psychiatric diagnosis: The seven pillars of RDoC.BMC Med. 2013; 11: 126
- Learning, memory and brain plasticity in posttraumatic stress disorder: Context matters.Restor Neurol Neurosci. 2014; 32: 95-102
- Aversive imagery in posttraumatic stress disorder: Trauma recurrence, comorbidity, and physiological reactivity.Biol Psychiatry. 2010; 67: 346-356
- RDoC, DSM, and the reflex physiology of fear: A biodimensional analysis of the anxiety disorders spectrum.Psychophysiology. 2016; 53: 336-347
- Defensive mobilization in specific phobia: Fear specificity, negative affectivity, and diagnostic prominence.Biol Psychiatry. 2012; 72: 8-18
- A mechanism-oriented approach to psychopathology: The role of Pavlovian conditioning.Int J Psychophysiol. 2015; 98: 351-364
- Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation.Neurosci Biobehav Rev. 2016; 71: 48-57
- Learning models of PTSD: Theoretical accounts and psychobiological evidence.Int J Psychophysiol. 2015; 98: 594-605
- Genetic influences on the neural and physiological bases of acute threat: A Research Domain Criteria (RDoC) perspective.Am J Med Genet B Neuropsychiatr Genet. 2016; 171: 44-64
- Corticosteroid effects on cellular physiology of limbic cells.Brain Res. 2009; 1293: 91-100
- Stress and the brain: From adaptation to disease.Nat Rev Neurosci. 2005; 6: 463-475
- Glucocorticoids interact with emotion-induced noradrenergic activation in influencing different memory functions.Neuroscience. 2006; 138: 901-910
- Dynamic plasticity: The role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors.Neuroscience. 2013; 239: 214-227
- Corticosteroid receptor genetic polymorphisms and stress responsivity.Endocrine. 2005; 28: 263-270
- Interaction of early life stress and corticotropin-releasing hormone receptor gene: Effects on working memory.Biol Psychiatry. 2014; 76: 888-894
- Neurobiology of posttraumatic stress disorder.CNS Spectr. 2009; 14: 13-24
- Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: Effects on hypothalamic-pituitary-adrenal axis reactivity.Biol Psychiatry. 2009; 66: 681-685
- Association of FKBP5 polymorphisms and childhood abuse with risk of post-traumatic stress disorder symptoms in adults.JAMA. 2008; 299: 1291-1305
- Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions.Nat Neurosci. 2013; 16: 33-41
- Gene–environment interactions at the FKBP5 locus: Sensitive periods, mechanisms and pleiotropism.Genes Brain Behav. 2014; 13: 25-37
- Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.Nat Genet. 2004; 36: 1319-1325
- Stress-system genes and life stress predict cortisol levels and amygdala and hippocampal volumes in children.Neuropsychopharmacology. 2014; 39: 1245-1253
- Disclosure of traumas and psychosomatic processes.Soc Sci Med. 1988; 26: 327-332
- Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls.Eur J Neurosci. 2008; 28: 389-398
- FKBP5 and resistant attachment predict cortisol reactivity in infants: gene–environment interaction.Psychoneuroendocrinology. 2010; 35: 1454-1461
- Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample.Hum Brain Mapp. 2016; 37: 1602-1613
- Distribution of the glucocorticoid receptor in the human amygdala; Changes in mood disorder patients.Brain Struct Funct. 2014; 219: 1615-1626
- Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.Neuropsychopharmacology. 2010; 35: 1684-1692
- Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: Evidence from endocrine and gene expression studies.Arch Gen Psychiatry. 2011; 68: 901-910
- Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs.Psychoneuroendocrinology. 2011; 36: 484-494
- Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function.Life Sci. 1996; 58: 1683-1694
- Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation.J Neurosci. 2007; 27: 6956-6964
- Functional subsets of serotonergic neurones: Implications for control of the hypothalamic-pituitary-adrenal axis.J Neuroendocrinol. 2002; 14: 911-923
- Cortisol responses to emotional stress in men: Association with a functional polymorphism in the 5HTR2C gene.Biol Psychol. 2012; 89: 94-98
- A functional polymorphism in the HTR2C gene associated with stress responses: A validation study.Biol Psychol. 2014; 103: 317-321
- Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress II: Evidence from two samples.Psychoneuroendocrinology. 2016; 70: 142-151
- Influence of the serotonin transporter promoter gene and shyness on children’s cerebral responses to facial expressions.Arch Gen Psychiatry. 2005; 62: 85-94
- Interaction effect of D4 dopamine receptor gene and serotonin transporter promoter polymorphism on the cortisol stress response.Behav Neurosci. 2009; 123: 1288-1295
- Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.Science. 1996; 274: 1527-1531
- Genetically driven variation in serotonin uptake: Is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?.Biol Psychiatry. 1998; 44: 179-192
- The highs and lows of amygdala reactivity in bipolar disorders.Am J Psychiatry. 2012; 169: 780-783
- Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in post-traumatic stress disorder.BMC Psychiatry. 2011; 11: 76
- Interaction of the serotonin transporter-linked polymorphic region and environmental adversity: Increased amygdala-hypothalamus connectivity as a potential mechanism linking neural and endocrine hyperreactivity.Biol Psychiatry. 2012; 72: 49-56
- Neural mechanisms underlying 5-HTTLPR-related sensitivity to acute stress.Am J Psychiatry. 2012; 169: 397-405
- Smaller hippocampus volume is associated with short variant of 5-HTTLPR polymorphism in medication-free major depressive disorder patients.Neuropsychobiology. 2011; 63: 22-28
- Childhood stress, serotonin transporter gene and brain structures in major depression.Neuropsychopharmacology. 2010; 35: 1383-1390
- Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume.Neuropsychopharmacology. 2012; 37: 1848-1855
- No effect of 5HTTLPR or BDNF Val66Met polymorphism on hippocampal morphology in major depression.Genes Brain Behav. 2011; 10: 756-764
- Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain.Am J Hum Genet. 2004; 75: 807-821
- Catechol-O-methyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response.Psychiatr Genet. 2007; 17: 183-193
- Serotonin transporter gene variation and stressful life events impact processing of fear and anxiety.Int J Neuropsychopharmacol. 2012; 12: 393-401
- Catechol-O-methyltransferase modulation of cortisol secretion in psychiatrically at-risk and healthy adolescents.Psychiatr Genet. 2010; 20: 166-170
- Genetic variants within the dopaminergic system interact to modulate endocrine stress reactivity and recovery.Behav Brain Res. 2011; 216: 53-58
- Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala.PLoS One. 2012; 7e30481
- Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.Mol Psychiatry. 2009; 14: 681-695
- BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects.Mol Psychiatry. 2012; 17: 597-603
- The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: Incremental support for a genetic risk factor for depression.Psychol Med. 2009; 39: 1831-1839
- Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants.J Neurosci. 2012; 32: 4092-4101
- Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.J Neurosci. 1995; 15: 1768-1777
- Expression of brain-derived neurotrophic factor and its receptors in the median eminence cells with sensitivity to stress.Endocrinology. 2004; 145: 4737-4747
- Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.J Neurosci. 2011; 31: 4475-4483
- Stress sensitivity and resilience in the chronic mild stress rat model of depression; An in situ hybridization study.Brain Res. 2008; 1196: 41-52
- Brain-derived neurotrophic factor Val66Met polymorphism and plasma levels in road traffic accident survivors.Anxiety Stress Coping. 2016; 29: 616-629
- BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals.Transl Psychiatry. 2011; 1: e51
- Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients.Psychoneuroendocrinology. 2006; 31: 1019-1025
- The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.Psychoneuroendocrinology. 2010; 35: 949-953
- BDNF Val66Met polymorphism is associated with higher anticipatory cortisol stress response, anxiety, and alcohol consumption in healthy adults.Psychoneuroendocrinology. 2011; 36: 1562-1569
- BDNF Val66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields.Hum Brain Mapp. 2014; 35 (5776–5583)
- Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults.J Neural Transm (Vienna). 2011; 11: 249-257
- Impact of the BDNF Val66Met polymorphism on regional brain gray matter volumes: Relevance to the stress response.Psychiatry Investig. 2013; 10: 173-179
- BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions.Psychoneuroendocrinology. 2009; 34: 382-388
- Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress.Psychoneuroendocrinology. 2017; 79: 13-19
- Brain activation during script-driven imagery induced dissociative responses in PTSD: A functional magnetic resonance imaging investigation.Biol Psychiatry. 2002; 52: 305-311
- Neuropeptide S: A transmitter system in the brain regulating fear and anxiety.Neuropharmacology. 2009; 58: 29-34
- Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain.J Comp Neurol. 2007; 500: 84-102
- Neuropeptide S receptor gene—Converging evidence for a role in panic disorder.Mol Psychiatry. 2011; 16: 938-948
- A neuropeptide S receptor variant associated with overinterpretation of fear reactions: A potential neurogenetic basis for catastrophizing.Mol Psychiatry. 2010; 15: 1067-1074
- Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli.Neuropsychopharmacology. 2011; 36: 1879-1885
- Neuropeptide S receptor gene is associated with cortisol responses to social stress in humans.Biol Psychol. 2013; 93: 304-307
- Social effects of oxytocin in humans: Context and person matter.Trends Cogn Sci. 2011; 15: 301-309
- Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress.Biol Psychiatry. 2003; 54: 1389-1398
- Central nervous system effects of the neurohypophyseal hormones and related peptides.Front Neuroendocrinol. 1993; 14: 251-302
- Structure and expression of a human oxytocin receptor.Nature. 1992; 356: 526-529
- Variation in the oxytocin receptor gene influences neurocardiac reactivity to social stress and HPA function: A population based study.Horm Behav. 2012; 61: 134-139
- Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans.Proc Natl Acad Sci U S A. 2011; 108: 19937-19942
- Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress.J Psychiatr Res. 2014; 59: 93-100
- The functional neuroanatomy of PTSD: A critical review.Prog Brain Res. 2007; 167: 151-169
- Failure of extinction of fear responses in posttraumatic stress disorder: Evidence from second-order conditioning.Am J Psychiatry. 2007; 164: 1684-1692
- De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder.J Abnorm Psychol. 2000; 109: 290-298
- Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder.Psychol Med. 2005; 35: 791-806
- Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.Biol Psychiatry. 2009; 66: 1075-1082
- Deficient fear extinction memory in posttraumatic stress disorder.Neurobiol Learn Mem. 2016; 136: 116-126
- A twin study of the genetics of fear conditioning.Arch Gen Psychiatry. 2003; 60: 702-708
- Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.PLoS One. 2013; 22e63772
- Human fear acquisition deficits in relation to genetic variants of the corticotropin-releasing hormone receptor 1 and the serotonin transporter—revisited.Genes Brain Behav. 2016; 15: 209-220
- Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic-pituitary-adrenal axis: First evidence from two independent subsamples.Psychol Med. 2011; 42: 2325-2335
- Neural mechanism of a sex-specific risk variant for posttraumatic stress disorder in the type I receptor of the pituitary adenylate cyclase activating polypeptide.Biol Psychiatry. 2015; 78: 840-847
- Behavioral and central correlates of contextual fear learning and contextual modulation of cued fear in posttraumatic stress disorder.Int J Psychophysiol. 2015; 98: 584-593
- Impaired contextual modulation of memories in PTSD: An fMRI and psychophysiological study of extinction retention and fear renewal.J Neurosci. 2014; 34: 13435-13443
- Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20120192
- Genetic contributions of the serotonin transporter to social learning of fear and economic decision making.Soc Cogn Affect Neurosci. 2009; 4: 399-408
- Human fear conditioning is related to dopaminergic and serotonergic biological markers.Behav Neurosci. 2001; 115: 358-364
- Genetic gating of human fear learning and extinction: Possible implications for gene–environment interaction in anxiety disorder.Psychol Sci. 2009; 20: 198-206
- Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events.Soc Cogn Affect Neurosci. 2013; 8: 318-325
- The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity.Soc Cogn Affect Neurosci. 2015; 10: 700-707
- Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction.PLoS One. 2012; 7e44352
- Human fear reconsolidation and allelic differences in serotonergic and dopaminergic genes.Transl Psychiatry. 2012; 2: e76
- The functional 1019C/G HTR1A polymorphism and mechanisms of fear.Transl Psychiatry. 2014; 4: e490
- MAOA and mechanisms of panic disorder revisited: From bench to molecular psychotherapy.Mol Psychiatry. 2014; 19: 122-128
- Genetic influences on the acquisition and inhibition of fear.Int J Psychophysiol. 2015; 98: 499-505
- COMT val158met polymorphism links to altered fear conditioning and extinction are modulated by PTSD and childhood trauma.Depress Anxiety. 2018; 35: 32-42
- Empirical support for an involvement of the mesostriatal dopamine system in human fear extinction.Transl Psychiatry. 2011; 1: e12
- The D2 dopamine receptor gene variant C957T affects human fear conditioning and aversive priming.Genes Brain Behav. 2010; 9: 103-109
- Genetic variation in brain-derived neurotrophic factor and human fear conditioning.Genes Brain Behav. 2009; 8: 80-85
- The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder.BMC Psychiatry. 2010; 10: 99
- BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall.Soc Cogn Affect Neurosci. 2015; 10: 664-671
- A genetic variant BDNF polymorphism alters extinction learning in both mouse and human.Science. 2010; 327: 863-866
- Preventing the return of fear using reconsolidation update mechanisms depends on the Met-allele of the brain derived neurotrophic factor Val66Met polymorphism.Int J Neuropsychopharmacol. 2016; 19: pyv137
- The BDNF Val66Met polymorphism modulates the generalization of cued fear responses to a novel context.Neuropsychopharmacology. 2014; 39: 1187-1195
- Risk variant for schizophrenia in the neurogranin gene impacts on hippocampus activation during contextual fear conditioning.Mol Psychiatry. 2011; 16: 1072-1073
- Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: Effects on fear-potentiated startle.Front Behav Neurosci. 2013; 7: 31
- The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: A meta-analysis.Mol Psychiatry. 2013; 18: 1018-1024
- The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: A meta-analysis.Mol Psychiatry. 2013; 18: 512-520
- Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: Meta-analysis and new data.Biol Psychiatry. 2008; 63: 197-206
- Affect-modulated startle: Interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma.PLoS One. 2012; 7e39709
- Multilevel impact of the dopamine system on the emotion-potentiated startle reflex.Psychopharmacology. 2015; 232: 1983-1993
- Affect-modulated startle reflex and dopamine D4 receptor gene variation.Psychophysiology. 2010; 47: 25-33
- Long-term expression of human contextual fear and extinction memories involves amygdala, hippocampus and ventromedial prefrontal cortex: A reinstatement study in two independent samples.Soc Cogn Affect Neurosci. 2014; 9: 1973-1983
- Acquisition and generalization of fear conditioning are not modulated by the BDNF-val66met polymorphism in humans.Psychophysiology. 2012; 49: 713-719
- Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.PLoS Genet. 2014; 10e1004474
- The low single nucleotide polymorphism heritability of plasma and saliva cortisol levels.Psychoneuroendocrinology. 2017; 85: 88-95
- Largest GWAS of PTSD (N = 20 070) yields genetic overlap with schizophrenia and sex differences in heritability.Mol Psychiatry. 2018; 23: 666-673
- Genetic architectures of psychiatric disorders: The emerging picture and its implications.Nat Rev Genet. 2012; 13: 537-551
- Meta-analysis of genetic association studies.Trends Genet. 2004; 20: 439-444
- Power failure: Why small sample size undermines the reliability of neuroscience.Nat Rev Neurosci. 2013; 14: 365-376
- The three-hit concept of vulnerability and resilience: Towards understanding adaptation to early-life adversity outcome.Psychoneuroendocrinology. 2013; 38: 1858-1873
- The genetics and epigenetics of PTSD: Overview, recent advances, and future directions.Curr Opin Psychol. 2017; 14: 5-11
- Shifting towards a model of mGluR5 dysregulation in schizophrenia: Consequences for future schizophrenia treatment.Neuropharmacology. 2017; 115: 73-91
- Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression.Biol Psychiatry. 2010; 68: 818-824
Article info
Publication history
Published online: January 10, 2018
Accepted:
December 22,
2017
Received in revised form:
December 19,
2017
Received:
April 13,
2017
Identification
Copyright
© 2018 Society of Biological Psychiatry.
