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  • The International Journal of Neuropsychopharmacology, Volume 15, Issue 8
  • August 2012, pp. 1027-1036

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers

  • Kris H. Naudts (a1), Ruben T. Azevedo (a2), Anthony S. David (a2), Kees van Heeringen (a3) and Ayana A. Gibbs (a2) (a4)
  • DOI:
  • Published online: 19 August 2011

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.

Corresponding author
Address for correspondence: Dr A. A. Gibbs, Clinical Imaging Sciences Centre, University of Sussex, Falmer, Brighton BN1 9RR, UK. Tel.: 01273876702Fax: 01273877548Email:
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AK Anderson (2005). Affective influences on the attentional dynamics supporting awareness. Journal of Experimental Psychology: General 134, 258281.

AK Anderson , EA Phelps (2001). Lesions of the human amygdala impair enhanced perception of emotionally salient events. Nature 411, 305309.

E Arce , A Simmons , K Lovero , M Stein , (2008). Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology 196, 661672.

D Arnone , J Horder , P Cowen , C Harmer (2009). Early effects of mirtazapine on emotional processing. Psychopharmacology 203, 685691.

CG Beevers , AJ Ellis , TT Wells , JE McGeary (2010). Serotonin transporter gene promoter region polymorphism and selective processing of emotional images. Biological Psychology 83, 260265.

CG Beevers , BE Gibb , JE McGeary , IW Miller (2007). Serotonin transporter genetic variation and biased attention for emotional word stimuli among psychiatric inpatients. Journal of Abnormal Psychology 116, 208212.

CG Beevers , CN Marti , HJ Lee , DL Stote , (2011). Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information. Journal of Abnormal Psychology 120, 187197.

A Bertolino , G Arciero , V Rubino , V Latorre , (2005). Variation of human amygdala response during threatening stimuli as a function of 5′HTTLPR genotype and personality style. Biological Psychiatry 57, 15171525.

M Browning , C Reid , PJ Cowen , GM Goodwin , (2007). A single dose of citalopram increases fear recognition in healthy subjects. Journal of Psychopharmacology 21, 684690.

AB Brühl , T Kaffenberger , U Herwig (2009). Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants. Neuropsychopharmacology 35, 521533.

NS Burghardt , GM Sullivan , BS McEwen , JM Gorman , (2004). The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biological Psychiatry 55, 11711178.

T Canli , K Omura , B Haas , A Fallgatter , (2005). Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. Proceedings of the National Academy of Sciences USA 102, 1222412229.

A Caspi , AR Hariri , A Holmes , R Uher , (2010). Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. American Journal of Psychiatry 167, 509527.

A Caspi , K Sugden , TE Moffitt , A Taylor , (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386389.

HW Clement , D Gemsa , W Wesemann (1992). The effect of adrenergic drugs on serotonin metabolism in the nucleus raphe dorsalis of the rat, studied by in vivo voltammetry. European Journal of Pharmacology 217, 4348.

HJ Cordell (2009). Detecting gene–gene interactions that underlie human diseases. Nature Reviews Genetics 10, 392404.

T de Boer (1995). The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. International Clinical Psychopharmacology 10 (Suppl. 4), 1923.

T De Boer , F Nefkens , A Van Helvoirt (1994). The α2-adrenoceptor antagonist org 3770 enhances serotonin transmission in vivo. European Journal of Pharmacology 253, R5R6.

B De Martino , B Strange , R Dolan (2008). Noradrenergic neuromodulation of human attention for emotional and neutral stimuli. Psychopharmacology 197, 127136.

DJF de Quervain , IT Kolassa , V Ertl , PL Onyut , (2007). A deletion variant of the α2b-adrenoceptor is related to emotional memory in Europeans and Africans. Nature Neuroscience 10, 11371139.

C Firk , C Markus (2009). Differential effects of 5-HTTLPR genotypes on mood, memory, and attention bias following acute tryptophan depletion and stress exposure. Psychopharmacology 203, 805818.

E Fox , A Ridgewell , C Ashwin (2009). Looking on the bright side: biased attention and the human serotonin transporter gene. Proceedings of the Royal Society of London, Series B: Biological Sciences 276, 17471751.

A Gibbs , K Naudts , E Spencer , A David (2007). The role of dopamine in attentional and memory biases for emotional information. American Journal of Psychiatry 164, 16031609.

AA Gibbs , KH Naudts , RT Azevedo , AS David (2010). Deletion variant of α2b-adrenergic receptor gene moderates the effect of COMT val158met polymorphism on episodic memory performance. European Neuropsychopharmacology 20, 272275.

S Hamann , T Canli (2004). Individual differences in emotion processing. Current Opinion in Neurobiology 14, 233238.

AR Hariri , EM Drabant , KE Munoz , BS Kolachana , (2005). A susceptibility gene for affective disorders and the response of the human amygdala. Archives of General Psychiatry 62, 146152.

AR Hariri , VS Mattay , A Tessitore , B Kolachana , (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400403.

C Harmer , J Heinzen , U O'Sullivan , R Ayres , (2008). Dissociable effects of acute antidepressant drug administration on subjective and emotional processing measures in healthy volunteers. Psychopharmacology 199, 495502.

CJ Harmer , Z Bhagwagar , DI Perrett , BA Völlm , (2003). Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 28, 152.

CJ Harmer , GM Goodwin , PJ Cowen (2009). Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. British Journal of Psychiatry 195, 102108.

CJ Harmer , NC Shelley , PJ Cowen , GM Goodwin (2004). Increased positive vs. negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. American Journal of Psychiatry 161, 12561263.

G Hayward , GM Goodwin , PJ Cowen , CJ Harmer (2005). Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms. Biological Psychiatry 57, 517524.

A Heils , A Teufel , S Petri , G Stöber , (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry 66, 26212624.

A Heinz , DF Braus , MN Smolka , J Wrase , (2004). Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature Neuroscience 8, 2021.

X Hu , G Oroszi , J Chun , TL Smith , (2005). An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcoholism: Clinical and Experimental Research 29, 8–16.

XZ Hu , RH Lipsky , G Zhu , LA Akhtar , (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder. American Journal of Human Genetics 78, 815826.

XZ Hu , AJ Rush , D Charney , AF Wilson , (2007). Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Archives of General Psychiatry 64, 783792.

A Keil , N Ihssen (2004). Identification facilitation for emotionally arousing verbs during the attentional blink. Emotion 4, 2335.

JM Leppanen (2006). Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings. Current Opinion in Psychiatry 19, 3439.

K-P Lesch , D Bengel , A Heils , S Sabol , (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 15271531.

KP Lesch , L Gutknecht (2005). Pharmacogenetics of the serotonin transporter. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29, 10621073.

CR Markus , R De Raedt (2011). Differential effects of 5-HTTLPR genotypes on inhibition of negative emotional information following acute stress exposure and tryptophan challenge. Neuropsychopharmacology 36, 819826.

CR Markus , C Firk (2009). Differential effects of tri-allelic 5-HTTLPR polymorphisms in healthy subjects on mood and stress performance after tryptophan challenge. Neuropsychopharmacology 34, 26672674.

JL McGaugh (2004). The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience 27, 128.

FJ McMahon , S Buervenich , D Charney , R Lipsky , (2006). Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. American Journal of Human Genetics 78, 804814.

R Mongeau , P Blier , C Montigny (1993). In vivo electrophysiological evidence for tonic activation by endogenous noradrenaline of α2-adrenoceptors on 5-hydroxytryptamine terminals in the rat hippocampus. Naunyn-Schmiedeberg's Archives of Pharmacology 347, 266272.

MR Munafò , SM Brown , AR Hariri (2008). Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biological Psychiatry 63, 852857.

MR Munafò , EC Johnstone , B Mackintosh (2005). Association of serotonin transporter genotype with selective processing of smoking-related stimuli in current smokers and ex-smokers. Nicotine and Tobacco Research 7, 773778.

F Murphy , B Smith , P Cowen , T Robbins , (2002). The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology 163, 4253.

SE Murphy , R Norbury , U O'Sullivan , PJ Cowen , (2009 a). Effect of a single dose of citalopram on amygdala response to emotional faces. British Journal of Psychiatry 194, 535540.

SE Murphy , J Yiend , KJ Lester , PJ Cowen , (2009 b). Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy volunteers. International Journal of Neuropsychopharmacology 12, 169179.

NV Murthy , S Selvaraj , PJ Cowen , Z Bhagwagar , (2010). Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain. NeuroImage 52, 5054.

NCI-NHGRI Working Group on Replication in Association Studies (2007). Replicating genotype-phenotype associations. Nature 447, 655660.

R Norbury , CE Mackay , PJ Cowen , GM Goodwin , (2007). Short-term antidepressant treatment and facial processing: functional magnetic resonance imaging study. British Journal of Psychiatry 190, 531532.

DJ Nutt (2002). The neuropharmacology of serotonin and noradrenaline in depression. International Clinical Psychopharmacology 17, S1S12.

R Osinsky , M Reuter , Y Kupper , A Schmitz , (2008). Variation in the serotonin transporter gene modulates selective attention to threat. Emotion 8, 584588.

S Paddock , G Laje , D Charney , AJ Rush , (2007). Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. American Journal of Psychiatry 164, 11811188.

L Pezawas , A Meyer-Lindenberg , EM Drabant , B Verchinski , (2005). 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neuroscience 8, 828834.

N Praschak-Rieder , J Kennedy , AA Wilson , D Hussey , (2007). Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [11C]DASB positron emission tomography study. Biological Psychiatry 62, 327331.

B Rasch , K Spalek , S Buholzer , R Luechinger , (2009). A genetic variation of the noradrenergic system is related to differential amygdala activation during encoding of emotional memories. Proceedings of the National Academy of Sciences USA 106, 1919119196.

N Rawlings , R Norbury , P Cowen , C Harmer (2010). A single dose of mirtazapine modulates neural responses to emotional faces in healthy people. Psychopharmacology 212, 625634.

M Reimold , MN Smolka , G Schumann , A Zimmer , (2007). Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. Journal of Neural Transmission 114, 635639.

JP Roiser , MülU ler , L Clark , BJ Sahakian (2007). The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention. International Journal of Neuropsychopharmacology 10, 449461.

J Rubinsztein , R Rogers , WJ Riedel , MA Mehta , (2001). Acute dietary tryptophan depletion impairs maintenance of ‘affective set’ and delayed visual recognition in healthy volunteers. Psychopharmacology 154, 319326.

A Schosser , S Kasper (2009). The role of pharmacogenetics in the treatment of depression and anxiety disorders. International Clinical Psychopharmacology 24, 277288.

KM Small , KM Brown , SL Forbes , SB Liggett (2001). Polymorphic deletion of three intracellular acidic residues of the alpha 2B-adrenergic receptor decreases g protein-coupled receptor kinase-mediated phosphorylation and desensitization. Journal of Biological Chemistry 276, 49174922.

D Souery , J Amsterdam , C de Montigny , Y Lecrubier , (1999). Treatment resistant depression: methodological overview and operational criteria. European Neuropsychopharmacology 9, 8391.

RM Todd , AK Anderson (2009). The neurogenetics of remembering emotions past. Proceedings of the National Academy of Sciences USA 106, 1888118882.

RM Todd , DJ Palombo , B Levine , AK Anderson (2011). Genetic differences in emotionally enhanced memory. Neuropsychologia 49, 734744.

R Uher , P Huezo-Diaz , N Perroud , R Smith , (2009). Genetic predictors of response to antidepressants in the GENDEP project. Pharmacogenomics Journal 9, 225233.

CH van Dyck , RT Malison , JK Staley , LK Jacobsen , (2004). Central serotonin transporter availability measured with [123I]β-CIT SPECT in relation to serotonin transporter genotype. American Journal of Psychiatry 161, 525531.

P Vuilleumier (2005). How brains beware: neural mechanisms of emotional attention. Trends in Cognitive Sciences 9, 585594.

MM Wakeno , MM Kato , GM Okugawa , TP Fukuda , (2008). The alpha 2A-adrenergic receptor gene polymorphism modifies antidepressant responses to milnacipran. Journal of Clinical Psychopharmacology 28, 518524.

JR Wendland , BJ Martin , MR Kruse , KP Lesch , (2006). Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry 11, 224226.

M Willeit , N Praschak-Rieder , A Neumeister , W Pirker , (2000). [123I]-[beta]-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biological Psychiatry 47, 482489.

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