Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-25T23:02:18.235Z Has data issue: false hasContentIssue false

The effects of the CACNA1C rs1006737 A/G on affective startle modulation in healthy males

Published online by Cambridge University Press:  15 April 2020

E. Pasparakis
Affiliation:
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
E. Koiliari
Affiliation:
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
C. Zouraraki
Affiliation:
Department of Psychology, University of Crete, Rethymno, Crete, Greece
E.-M. Tsapakis
Affiliation:
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece Aghios Charalambos Mental Health Clinic, Heraklion, Crete, Greece
P. Roussos
Affiliation:
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece Department of Psychiatry, Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY10029, USA James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC) 130, West Kingsbridge Road, Bronx, NY10468, USA
S.G. Giakoumaki
Affiliation:
Department of Psychology, University of Crete, Rethymno, Crete, Greece
P. Bitsios*
Affiliation:
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
*
*Corresponding author. Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, 71003 Crete, Greece. Tel.: +30 28 10 39 46 10; fax: +30 28 10 39 46 06. E-mail address:[email protected] (P. Bitsios).
Get access

Abstract

Background:

The CACNA1C rs1006737 risk A allele has been associated with affective psychoses and functional studies indicate that it is associated with increased hippocampal/amygdala activity during emotional face-processing. Here we studied the impact of the risk A allele on affective startle modulation.

Methods:

Hundred and ninety-four healthy males stratified for their CACNA1C rs1006737 genotype (GG:111, GA:67, AA:16) were presented with 18 pleasant, 18 unpleasant and 18 neutral pictures with acoustic probes (104 dB) occurring during 12 pictures in each affective category. Baseline startle was assessed during blank screens. State mood was self-rated on arrival, pre- and post-test and the emotional valence and arousal of affective pictures at post-test.

Results:

Relative to the other genotypes, risk A allele homozygotes presented with higher anxiety/negative affect at pre-test, reduced and exaggerated physiological responses to the pleasant and negative pictures respectively, negative affect with reduced arousal at post-test and rated the affective pictures as less arousing and inconsistently to their physiological responses (all P < 0.05). Sustained contextual negative mood predicted reduced baseline and affective startle reactivity in the AA group.

Conclusions:

Healthy homozygous males for the risk A allele appear to have marked contextual sensitivity, affective reactivity akin to anxiety and depression and inefficient emotional appraisal. Our findings provide phenotypic detail of the CACNA1C AA genotype in non-symptomatic individuals, which suggest primary effects in emotional circuitry, consistent with previously documented alterations in hippocampal/amygdala processing.

Type
Original article
Copyright
Copyright © Elsevier Masson SAS 2015

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aldhafeeri, FM, Mackenzie, I, Kay, T, Alghamdi, J, Sluming, VRegional brain responses to pleasant and unpleasant IAPS pictures: different networks. Neurosci Lett 2012;512(2):9498.CrossRefGoogle ScholarPubMed
Allen, NB, Trinder, J, Brennan, CAffective startle modulation in clinical depression: preliminary findings. Biol Psychiatry 1999;46(4):542550.CrossRefGoogle ScholarPubMed
Almeida, JR, Versace, A, Hassel, S, Kupfer, DJ, Phillips, MLElevated amygdala activity to sad facial expressions: a state marker of bipolar but not unipolar depression. Biol Psychiatry 2010;67(5):414421.CrossRefGoogle Scholar
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000. [text revision].Google Scholar
Beck, DA, Koenig, HGMinor depression: a review of the literature. Int J Psychiatry Med 1996;26(2):177209.CrossRefGoogle ScholarPubMed
Bhat, S, Dao, DT, Terrillion, CE, Arad, M, Smith, RJ, Soldatov, NMet al.CACNA1C (Ca(v)1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol 2012;99(1):114.CrossRefGoogle ScholarPubMed
Bigos, KL, Mattay, VS, Callicott, JH, Straub, RE, Vakkalanka, R, Kolachana, Bet al.Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch Gen Psychiatry 2010;67(9):939945.CrossRefGoogle ScholarPubMed
Bond, AJ, Lader, MHThe use of analogue scales in rating subjective feelings. Br J Med Psychol 1974; 47: 211218.CrossRefGoogle Scholar
Bradley, MM, Cuthbert, BN, Lang, PJStartle reflex modification: emotion or attention?. Psychophysiology 1990;27(5):513522.CrossRefGoogle ScholarPubMed
Bylsma, LM, Morris, BH, Rottenberg, JA meta-analysis of emotional reactivity in major depressive disorder. Clin Psychol Rev 2008;28(4):676691.CrossRefGoogle ScholarPubMed
Callicott, JH, Mattay, VS, Verchinski, BA, Marenco, S, Egan, MF, Weinberger, DRComplexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry 2003;160(12):22092215.CrossRefGoogle ScholarPubMed
Celikel, FC, Kose, S, Erkorkmaz, U, Sayar, K, Cumurcu, BE, Cloninger, CRAlexithymia and temperament and character model of personality in patients with major depressive disorder. Compr Psychiatry 2010;51(1):6470.CrossRefGoogle ScholarPubMed
Clark, LA, Watson, DTripartite model of anxiety and depression: psychometric evidence and taxonomic implications. J Abnorm Psychol 1991;100(3):316336.CrossRefGoogle ScholarPubMed
Cook, EW 3rd. Hawk, LW Jr., Davis, TL, Stevenson, VEAffective individual differences and startle reflex modulation. J Abnorm Psychol 1991;100(1):513.CrossRefGoogle ScholarPubMed
Cook, EW 3rd. Davis, TL, Hawk, LW, Spence, EL, Gautier, CHFearfulness and startle potentiation during aversive visual stimuli. Psychophysiology 1992;29(6):633645.CrossRefGoogle ScholarPubMed
Curtis, CE, Lebow, B, Lake, DS, Katsanis, J, Iacono, WGAcoustic startle reflex in schizophrenia patients and their first-degree relatives: evidence of normal emotional modulation. Psychophysiology 1999;36(4):469475.CrossRefGoogle ScholarPubMed
Dao, DT, Mahon, PB, Cai, X, Kovacsics, CE, Blackwell, RA, Arad, Met al.Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Biol Psychiatry 2010;68(9):801810.CrossRefGoogle ScholarPubMed
Deng, Y, Ma, X, Tang, QBrain response during visual emotional processing: an fMRI study of alexithymia. Psychiatry Res 2013;213(3):225229.CrossRefGoogle ScholarPubMed
Ebner-Priemer, UW, Badeck, S, Beckmann, C, Wagner, A, Feige, B, Weiss, Iet al.Affective dysregulation and dissociative experience in female patients with borderline personality disorder: a startle response study. J Psychiatr Res 2005;39(1):8592.CrossRefGoogle ScholarPubMed
Elliot, AJ, Payen, V, Brisswalter, J, Cury, F, Thayer, JFA subtle threat cue, heart rate variability, and cognitive performance. Psychophysiology 2011;48(10):13401345.CrossRefGoogle ScholarPubMed
Erk, S, Meyer-Lindenberg, A, Schnell, K, Opitz von Boberfeld, C, Esslinger, C, Kirsch, Pet al.Brain function in carriers of a genome-wide supported bipolar disorder variant. Arch Gen Psychiatry 2010;67(8):803811.CrossRefGoogle ScholarPubMed
Eshel, N, Roiser, JPReward and punishment processing in depression. Biol Psychiatry 2010;68(2):118124.CrossRefGoogle ScholarPubMed
Eysenck, HJExtraversion and the acquisition of eyeblink and GSR conditioned responses. Psychol Bull 1965; 63: 258270.CrossRefGoogle ScholarPubMed
Fanselow, MSContextual fear, gestalt memories, and the hippocampus. Behav Brain Res 2000;110(1–2):7381.CrossRefGoogle ScholarPubMed
Ferreira, MA, O’Donovan, MC, Meng, YA, Jones, IR, Ruderfer, DM, Jones, Let al.Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):10561058.CrossRefGoogle ScholarPubMed
Fogley, R, Warman, D, Lysaker, PHAlexithymia in schizophrenia: associations with neurocognition and emotional distress. Psychiatry Res 2014;218(1–2):16.CrossRefGoogle ScholarPubMed
Giakoumaki, SG, Bitsios, P, Frangou, S, Roussos, P, Aasen, I, Galea, Aet al.Low baseline startle and deficient affective startle modulation in remitted bipolar disorder patients and their unaffected siblings. Psychophysiology 2010;47(4):659668.Google ScholarPubMed
Giakoumaki, SG, Roussos, P, Tsapakis, EM, Koiliari, E, Pasparakis, E, Zouraraki, Cet al.Cognitive and personality analysis of startle reactivity in a large cohort of healthy males. Biol Psychol 2013;94(3):582591.CrossRefGoogle Scholar
Green, EK, Grozeva, D, Jones, I, Jones, L, Kirov, G, Caesar, Set al.The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 2010;15(10):10161022.CrossRefGoogle ScholarPubMed
Grillon, CStartle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 2002;52(10):958975.CrossRefGoogle ScholarPubMed
Grillon, C, Baas, JA review of the modulation of the startle reflex by affective states and its application in psychiatry. Clin Neurophysiol 2003;114(9):15571579.CrossRefGoogle Scholar
Grillon, C, Pine, DS, Baas, JM, Lawley, M, Ellis, V, Charney, DSCortisol and DHEAS are associated with startle potentiation during aversive conditioning in humans. Psychopharmacology 2006;186(3):434441.CrossRefGoogle ScholarPubMed
Grillon, C, Franco-Chaves, JA, Mateus, CF, Ionescu, DF, Zarate, CAMajor depression is not associated with blunting of aversive responses; evidence for enhanced anxious anticipation. PLoS One 2013;8(8):e70969CrossRefGoogle Scholar
Hazlett, EA, Speiser, LJ, Goodman, M, Roy, M, Carrizal, M, Wynn, JKet al.Exaggerated affect-modulated startle during unpleasant stimuli in borderline personality disorder. Biol Psychiatry 2007;62(3):250255.CrossRefGoogle ScholarPubMed
Heller, W, Nitscke, JBRegional brain activity in emotion: a framework for understanding cognition in depression. Cogn Emot 1997;11(5–6):637661.CrossRefGoogle Scholar
Hettema, JM, Annas, P, Neale, MC, Kendler, KS, Fredrikson, MA twin study of the genetics of fear conditioning. Arch Gen Psychiatry 2003; 60: 702708CrossRefGoogle ScholarPubMed
Hughes, JW, York, KM, Li, Q, Freedland, KE, Carney, RM, Sheps, DSDepressive symptoms predict heart rate recovery after exercise treadmill testing in patients with coronary artery disease: results from the Psychophysiological Investigation of Myocardial Ischemia Study. Psychosom Med 2008;70(4):456460.CrossRefGoogle ScholarPubMed
Jogia, J, Ruberto, G, Lelli-Chiesa, G, Vassos, E, Maierú, M, Tatarelli, Ret al.The impact of the CACNA1C gene polymorphism on frontolimbic function in bipolar disorder. Mol Psychiatry 2011;16(11):10701071.CrossRefGoogle ScholarPubMed
Karukivi, M, Hautala, L, Kaleva, O, Haapasalo-Pesu, KM, Liuksila, PR, Joukamaa, Met al.Alexithymia is associated with anxiety among adolescents. J Affect Disord 2010;125(1–3):383387.CrossRefGoogle ScholarPubMed
Kaviani, H, Gray, JA, Checkley, SA, Raven, PW, Wilson, GD, Kumari, VAffective modulation of the startle response in depression: influence of the severity of depression, anhedonia, and anxiety. J Affect Disord 2004;83(1):2131.CrossRefGoogle ScholarPubMed
Lang, PJBehavioral treatment and bio-behavioral assessment: computer applications. Sidowski, JB, Johnson, JH, Williams, TATechnology in mental health care delivery systems. Norwood, NJ: Ablex Publishing; 1980. 119137.Google Scholar
Lang, PJ, Bradley, MM, Cuthbert, BNEmotion, attention, and the startle reflex. Psychol Rev 1990; 97: 377395CrossRefGoogle ScholarPubMed
Ledoux, JE, Muller, JEmotional memory and psychopathology. Philos Trans R Soc Lond B Biol Sci 1997;352(1362):17191726.Google ScholarPubMed
Lee, I, Lee, CHContextual behavior and neural circuits. Front Neural Circuits 2013;7:84 10.3389/fncir.2013.00084 [eCollection 2013].CrossRefGoogle ScholarPubMed
Leweke, F, Leichsenring, F, Kruse, J, Hermes, SIs alexithymia associated with specific mental disorders?. Psychopathology 2012;45(1):2228.CrossRefGoogle ScholarPubMed
Limberg, A, Barnow, S, Freyberger, HJ, Hamm, AOEmotional vulnerability in borderline personality disorder is cue specific and modulated by traumatization. Biol Psychiatry 2011;69(6):574582.CrossRefGoogle ScholarPubMed
Mardaga, S, Hansenne, MAutonomic aspect of emotional response in depressed patients: relationships with personality. Neurophysiol Clin 2009;39(4–5):209216.CrossRefGoogle ScholarPubMed
Maren, S, Phan, KL, Liberzon, IThe contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 2013;14(6):417428.CrossRefGoogle ScholarPubMed
McTeague, LM, Lang, PJThe anxiety spectrum and the reflex physiology of defense: from circumscribed fear to broad distress. Depress Anxiety 2012;29(4):264281.CrossRefGoogle ScholarPubMed
Meyer-Lindenberg, A, Weinberger, DRIntermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006;7(10):818827.CrossRefGoogle ScholarPubMed
Nesse, RMIs depression an adaptation?. Arch Gen Psychiatry 2000;57(1):1420.CrossRefGoogle ScholarPubMed
Nissen, C, Holz, J, Blechert, J, Feige, B, Riemann, D, Voderholzer, Uet al.Learning as a model for neural plasticity in major depression. Biol Psychiatry 2010;68(6):544552.CrossRefGoogle ScholarPubMed
Nyegaard, M, Demontis, D, Foldager, L, Hedemand, A, Flint, TJ, Sørensen, KMet al.CACNA1C (rs1006737) is associated with schizophrenia. Mol Psychiatry 2010;15(2):119121.CrossRefGoogle ScholarPubMed
O’Brien-Simpson, L, Di Parsia, P, Simmons, JG, Allen, NBRecurrence of major depressive disorder is predicted by inhibited startle magnitude while recovered. J Affect Disord 2009;112(1–3):243249.CrossRefGoogle ScholarPubMed
Pauli, P, Conzelmann, A, Mucha, RF, Weyers, P, Baehne, CG, Fallgatter, AJet al.Affect-modulated startle reflex and dopamine D4 receptor gene variation. Psychophysiology 2010;47(1):2533.CrossRefGoogle ScholarPubMed
Perrier, E, Pompei, F, Ruberto, G, Vassos, E, Collier, D, Frangou, SInitial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder. Eur Psychiatry 2011;26(3):135137.CrossRefGoogle ScholarPubMed
Pritchard, JK, Stephens, M, Donnelly, PInference of population structure using multilocus genotype data. Genetics 2000;155(2):945959.Google ScholarPubMed
Ripke, S, O’Dushlaine, C, Chambert, K, Moran, JL, Kähler, AK, Akterin, Set al.Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 2013;45(10):11501159.CrossRefGoogle Scholar
Rottenberg, J, Kasch, KL, Gross, JJ, Gotlib, IHSadness and amusement reactivity differentially predict concurrent and prospective functioning in major depressive disorder. Emotion 2002;2(2):135146.CrossRefGoogle ScholarPubMed
Rottenberg, J, Gross, JJ, Gotlib, IHEmotion context insensitivity in major depressive disorder. J Abnorm Psychol 2005;114(4):627639.CrossRefGoogle ScholarPubMed
Roussos, P, Giakoumaki, SG, Bitsios, PCognitive and emotional processing in high novelty seeking associated with the L-DRD4 genotype. Neuropsychologia 2009;47(7):16541659.CrossRefGoogle ScholarPubMed
Roussos, P, Giakoumaki, SG, Bitsios, PA risk PRODH haplotype affects sensorimotor gating, memory, schizotypy, and anxiety in healthy male subjects. Biol Psychiatry 2009;65(12):10631070.CrossRefGoogle ScholarPubMed
Roussos, P, Giakoumaki, SG, Georgakopoulos, A, Robakis, NK, Bitsios, PThe CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males. Bipolar Disord 2011;13(3):250259.CrossRefGoogle ScholarPubMed
Roussos, P, Bitsios, P, Giakoumaki, SG, McClure, MM, Hazlett, EA, New, ASet al.CACNA1C as a risk factor for schizotypal personality disorder and schizotypy in healthy individuals. Psychiatry Res 2013;206(1):122123.CrossRefGoogle ScholarPubMed
Roussos, P, Mitchell, AC, Voloudakis, G, Fullard, JF, Pothula, VM, Tsang, Jet al.A role for non-coding variation in schizophrenia. Cell Rep 2014;9(4):14171429.CrossRefGoogle Scholar
Sandi, C, Richter-Levin, GFrom high anxiety trait to depression: a neurocognitive hypothesis. Trends Neurosci 2009;32(6):312320.CrossRefGoogle ScholarPubMed
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511(7510):421427.CrossRefGoogle Scholar
Schlenker, R, Cohen, R, Hopmann, GAffective modulation of the startle reflex in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 1995;245(6):309318.CrossRefGoogle ScholarPubMed
Sklar, P, Smoller, JW, Fan, J, Ferreira, MA, Perlis, RH, Chambert, Ket al.Whole-genome association study of bipolar disorder. Mol Psychiatry 2008;13(6):558569.CrossRefGoogle ScholarPubMed
Sloan, DM, Strauss, ME, Wisner, KLDiminished response to pleasant stimuli by depressed women. J Abnorm Psychol 2001;110(3):488493.CrossRefGoogle ScholarPubMed
Smith, JC, Bradley, MM, Lang, PJState anxiety and affective physiology: effects of sustained exposure to affective pictures. Biol Psychol 2005;69(3):247260.CrossRefGoogle ScholarPubMed
Vaidyanathan, U, Malone, SM, Miller, MB, McGue, M, Iacono, WGHeritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: a genome-wide association study. Psychophysiology 2014;51(12):12851299.CrossRefGoogle ScholarPubMed
Wang, F, McIntosh, AM, He, Y, Gelernter, J, Blumberg, HPThe association of genetic variation in CACNA1C with structure and function of a frontotemporal system. Bipolar Disord 2011;13(7–8):696700.CrossRefGoogle ScholarPubMed
Wessa, M, Linke, J, Witt, SH, Nieratschker, V, Esslinger, C, Kirsch, Pet al.The CACNA1C risk variant for bipolar disorder influences limbic activity. Mol Psychiatry 2010;15(12):11261127.CrossRefGoogle ScholarPubMed
Whalley, HC, McKirdy, J, Romaniuk, L, Sussmann, J, Johnstone, EC, Wan, HIet al.Functional imaging of emotional memory in bipolar disorder and schizophrenia Bipolar Disord 2009;11(8):840856.CrossRefGoogle Scholar
Supplementary material: File

Pasparakis et al. supplementary material

Tables S1-S3

Download Pasparakis et al. supplementary material(File)
File 83.5 KB
Submit a response

Comments

No Comments have been published for this article.