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Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort

  • Trina M. Norden-Krichmar (a1) (a2), Ian R. Gizer (a3), Evelyn Phillips (a1), Kirk C. Wilhelmsen (a4), Nicholas J. Schork (a5) and Cindy L. Ehlers (a1)...


Neurophysiological measurements of the response to pre-pulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic pre-pulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study, we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18–30 years) MA men (n = 170), and women (n = 250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to pre-pulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the pre-pulse/startle response in this cohort.

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      Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort
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Corresponding author

address for correspondence: Cindy L. Ehlers, Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037 USA. E-mail:


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Affymetrix. (2011). Affymetrix: Best practice supplement to axiom genotyping solution data analysis user guide rev. 1 (vol. 1, pp. 133). Santa Clara, CA: Author.
Bagney, A., Rodriguez-Jimenez, R., Martinez-Gras, I., Sanchez-Morla, E. M., Santos, J. L., Jimenez-Arriero, M. A., . . . Parg, . (2013). Negative symptoms and executive function in schizophrenia: Does their relationship change with illness duration? Psychopathology, 46, 241248.
Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2005). Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics, 21, 263265.
Bauer, L. O. (1997). Frontal P300 decrements, childhood conduct disorder, family history, and the prediction of relapse among abstinent cocaine abusers. Drug and Alcohol Dependence, 44, 110.
Braff, D. L., Geyer, M. A., Light, G. A., Sprock, J., Perry, W., Cadenhead, K. S., . . . Swerdlow, N. R. (2001a). Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia. Schizophrenia Research, 49, 171178.
Braff, D. L., Geyer, M. A., & Swerdlow, N. R. (2001b). Human studies of prepulse inhibition of startle: Normal subjects, patient groups, and pharmacological studies. Psychopharmacology, 156, 234258.
Bucholz, K. K., Cadoret, R., Cloninger, C. R., Dinwiddie, S. H., Hesselbrock, V. M., Nurnberger, J. I. Jr., . . . Schuckit, M. A. (1994). A new, semi-structured psychiatric interview for use in genetic linkage studies: A report on the reliability of the SSAGA. Journal of Studies on Alcohol, 55, 149158.
Campbell, L. E., Hughes, M., Budd, T. W., Cooper, G., Fulham, W. R., Karayanidis, F., . . . Schall, U. (2007). Primary and secondary neural networks of auditory prepulse inhibition: A functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response. The European Journal of Neuroscience, 26, 23272333.
Castaneda, A. E., Tuulio-Henriksson, A., Marttunen, M., Suvisaari, J., & Lonnqvist, J. (2008). A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. Journal of Affective Disorders, 106, 127.
Chan, S. K. W., Chan, K. K. S., Hui, C. L., Wong, G. H. Y., Chang, W. C., Lee, E. H. M., . . . Chen, E. Y. H. (2014). Correlates of insight with symptomatology and executive function in patients with first-episode schizophrenia-spectrum disorder: A longitudinal perspective. Psychiatry Research, 216, 177184.
Christoforou, A., Le Hellard, S., Thomson, P. A., Morris, S. W., Tenesa, A., Pickard, B. S., . . . Evans, K. L. (2007). Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia. Molecular Psychiatry, 12, 10111025.
Crawley, J. N., & Corwin, R. L. (1994). Biological actions of cholecystokinin. Peptides, 15, 731755.
Criado, J. R., & Ehlers, C. L. (2007). Electrophysiological responses to affective stimuli in Mexican Americans: Relationship to alcohol dependence and personality traits. Pharmacology, Biochemistry, and Behavior, 88, 148157.
Criado, J. R., Gizer, I. R., Edenberg, H. J., & Ehlers, C. L. (2014). CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women. Twin Research and Human Genetics, 17, 8088.
De Koning, M. B., Bloemen, O. J., Van Duin, E. D., Booij, J., Abel, K. M., De Haan, L., . . . Van Amelsvoort, T. A. (2014). Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis. Journal of Psychopharmacology, 28, 553560.
De Pascalis, V., Cozzuto, G., & Russo, E. (2013). Effects of personality trait emotionality on acoustic startle response and prepulse inhibition including N100 and P200 event-related potential. Clinical Neurophysiology, 124, 292305.
Ehlers, C. L., Gilder, D. A., Criado, J. R., & Caetano, R. (2009). Acculturation stress, anxiety disorders, and alcohol dependence in a select population of young adult Mexican Americans. Journal of Addiction Medicine, 3, 227233.
Ehlers, C. L., Gilder, D. A., Criado, J. R., & Caetano, R. (2010). Sleep quality and alcohol-use disorders in a select population of young-adult Mexican Americans. Journal of Studies on Alcohol and Drugs, 71, 879884.
Ehlers, C. L., Liang, T., & Gizer, I. R. (2012). ADH and ALDH polymorphisms and alcohol dependence in Mexican and Native Americans. American Journal of Drug and Alcohol Abuse, 38, 389394.
Ehlers, C. L., & Phillips, E. (2007). Association of EEG alpha variants and alpha power with alcohol dependence in Mexican American young adults. Alcohol, 41, 1320.
Ehlers, C. L., Phillips, E., Criado, J. R., & Gilder, D. A. (2011). N4 component responses to pre-pulse startle stimuli in young adults: Relationship to alcohol dependence. Psychiatry Research, 188, 237244.
Ehlers, C. L., Stouffer, G. M., & Gilder, D. A. (2014). Associations between a history of binge drinking during adolescence and self-reported responses to alcohol in young adult native and Mexican Americans. Alcoholism, Clinical and Experimental Research, 38, 20392047.
Eisenberg, D. P., & Berman, K. F. (2010). Executive function, neural circuitry, and genetic mechanisms in schizophrenia. Neuropsychopharmacology, 35, 258277.
Encode Project Consortium. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 5774.
Erol, A., Kosger, F., Putgul, G., & Ersoy, B. (2014). Ventral prefrontal executive function impairment as a potential endophenotypic marker for bipolar disorder. Nordic Journal of Psychiatry, 68, 1823.
Feifel, D., Priebe, K., & Shilling, P. D. (2001). Startle and sensorimotor gating in rats lacking CCK-A receptors. Neuropsychopharmacology, 24, 663670.
Feifel, D., Reza, T. L., Wustrow, D. J., & Davis, M. D. (1999). Novel antipsychotic-like effects on prepulse inhibition of startle produced by a neurotensin agonist. Journal of Pharmacology and Experimental Therapeutics, 288, 710713.
Feifel, D., & Swerdlow, N. R. (1997). The modulation of sensorimotor gating deficits by mesolimbic cholecystokinin. Neuroscience Letters, 229, 58.
Fendt, M., Koch, M., Kungel, M., & Schnitzler, H. U. (1995). Cholecystokinin enhances the acoustic startle response in rats. Neuroreport, 6, 20812084.
Fendt, M., Li, L., & Yeomans, J. S. (2001). Brain stem circuits mediating prepulse inhibition of the startle reflex. Psychopharmacology, 156, 216224.
Fernandez-Serrano, M. J., Perez-Garcia, M., Schmidt Rio-Valle, J., & Verdejo-Garcia, A. (2010). Neuropsychological consequences of alcohol and drug abuse on different components of executive functions. Journal of Psychopharmacology, 24, 13171332.
Ferreira, M. A., & Purcell, S. M. (2009). A multivariate test of association. Bioinformatics, 25, 132133.
Filion, D. L., Dawson, M. E., & Schell, A. M. (1998). The psychological significance of human startle eyeblink modification: A review. Biological Psychology, 47, 143.
Filion, D. L., Kelly, K. A., & Hazlett, E. A. (1999). Behavioral analogies of short lead interval startle inhibition. In Dawson, M. E., Schell, A. M., & Bohmelt, A. H. (Eds.), Startle modification: Implications for neuroscience, cognitive science, and clinical science (pp. 269283). Cambridge, UK: Cambridge University Press.
Ford, J. M., Roth, W. T., Menon, V., & Pfefferbaum, A. (1999). Failures of automatic and strategic processing in schizophrenia: Comparisons of event-related brain potential and startle blink modification. Schizophrenia Research, 37, 149163.
Ford, J. M., White, P., Lim, K. O., & Pfefferbaum, A. (1994). Schizophrenics have fewer and smaller P300s: A single-trial analysis. Biological Psychiatry, 35, 96103.
Geyer, M. A., & Swerdlow, N. R. (2001). Measurement of startle response, prepulse inhibition, and habituation. Current Protocols in Neuroscience, 3, 8.7.1–8.7.15.
Gierski, F., Hubsch, B., Stefaniak, N., Benzerouk, F., Cuervo-Lombard, C., Bera-Potelle, C., . . . Limosin, F. (2013). Executive functions in adult offspring of alcohol-dependent probands: Toward a cognitive endophenotype? Alcoholism, Clinical and Experimental Research, 37 (Suppl. 1), E356E363.
Gosso, F. M., de Geus, E. J., Polderman, T. J., Boomsma, D. I., Posthuma, D., & Heutink, P. (2007). Exploring the functional role of the CHRM2 gene in human cognition: Results from a dense genotyping and brain expression study. BMC Medical Genetics, 8, 66.
Grillon, C., Morgan, C. A., Southwick, S. M., Davis, M., & Charney, D. S. (1996). Baseline startle amplitude and prepulse inhibition in Vietnam veterans with posttraumatic stress disorder. Psychiatry Research, 64, 169178.
Hesselbrock, M., Easton, C., Bucholz, K. K., Schuckit, M., & Hesselbrock, V. (1999). A validity study of the SSAGA — A comparison with the SCAN. Addiction, 94, 13611370.
Holmen, A., Juuhl-Langseth, M., Thormodsen, R., Ueland, T., Agartz, I., Sundet, K., . . . Melle, I. (2012). Executive function in early- and adult onset schizophrenia. Schizophrenia Research, 142, 177182.
Hsieh, M. H., Swerdlow, N. R., & Braff, D. L. (2006). Effects of background and prepulse characteristics on prepulse inhibition and facilitation: Implications for neuropsychiatric research. Biological Psychiatry, 59, 555559.
Josselyn, S. A., Frankland, P. W., Petrisano, S., Bush, D. E., Yeomans, J. S., & Vaccarino, F. J. (1995). The CCKB antagonist, L-365260, attenuates fear-potentiated startle. Peptides, 16, 13131315.
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., . . . Haussler, D. (2002). The human genome browser at UCSC. Genome Research, 12, 9961006.
Knott, V. J., Mahoney, C., Gunnarsson, T., Bradwejn, J., & Shlik, J. (2002). Acute cholecystokinin effects on event-related potentials in healthy volunteers. Human Psychopharmacology, 17, 285291.
Knott, V., Mahoney, C., Bradwejn, J., Shlik, J., & Gunnarsson, T. (2003). Effects of acute cholecystokinin infusion on hemispheric EEG asymmetry and coherence in healthy volunteers. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 27, 179184.
Kohl, S., Heekeren, K., Klosterkotter, J., & Kuhn, J. (2013). Prepulse inhibition in psychiatric disorders — Apart from schizophrenia. Journal of Psychiatric Research, 47, 445452.
Konturek, S. J., Brzozowski, T., Pytko-Polonczyk, J., & Drozdowicz, D. (1995). Exogenous and endogenous cholecystokinin protects gastric mucosa against the damage caused by ethanol in rats. European Journal of Pharmacology, 273, 5762.
Koszycki, D., Prichard, Z., Fiocco, A. J., Shlik, J., Kennedy, J. L., & Bradwejn, J. (2012). CCK-B receptor gene and response to cholecystokinin-tetrapeptide in healthy volunteers. Peptides, 35, 913.
Kulkarni, S., Jain, S., Reddy, Y. C. J., Kumar, K. J., & Kandavel, T. (2010). Impairment of verbal learning and memory and executive function in unaffected siblings of probands with bipolar disorder. Bipolar Disorders, 12, 647656.
Kumari, V., Antonova, E., Zachariah, E., Galea, A., Aasen, I., Ettinger, U., . . . Sharma, T. (2005). Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans. Neuroimage, 26, 10521058.
Li, M. X., Yeung, J. M., Cherny, S. S., & Sham, P. C. (2012). Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets. Human Genetics, 131, 747756.
Loeber, S., Vollstadt-Klein, S., von der Goltz, C., Flor, H., Mann, K., & Kiefer, F. (2009). Attentional bias in alcohol-dependent patients: The role of chronicity and executive functioning. Addiction Biology, 14, 194203.
Ludewig, K., Ludewig, S., Seitz, A., Obrist, M., Geyer, M. A., & Vollenweider, F. X. (2003). The acoustic startle reflex and its modulation: Effects of age and gender in humans. Biological Psychology, 63, 311323.
Marin, M., Ponce, G., Martinez-Gras, I., Koeneke, A., Curivil, P., Jimenez-Arriero, M. A., . . . Rubio, G. (2012). Impairments of prepulse inhibition of the startle response in abstinent alcoholic male patients. Alcohol and Alcoholism, 47, 545551.
Maron, E., Toru, I., Tasa, G., Must, A., Toover, E., Lang, A., . . . Shlik, J. (2008). Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers. Neuroscience Letters, 446, 8892.
Maurage, P., de Timary, P., Billieux, J., Collignon, M., & Heeren, A. (2014). Attentional alterations in alcohol dependence are underpinned by specific executive control deficits. Alcoholism, Clinical and Experimental Research, 38, 21052112.
Maurano, M. T., Humbert, R., Rynes, E., Thurman, R. E., Haugen, E., Wang, H., . . . Stamatoyannopoulos, J. A. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science, 337, 11901195.
Miyasaka, K., Yoshida, Y., Matsushita, S., Higuchi, S., Maruyama, K., Niino, N., . . . Funakoshi, A. (2004). Association of cholecystokinin-A receptor gene polymorphism with alcohol dependence in a Japanese population. Alcohol and Alcoholism, 39, 2528.
Neuner, I., Stocker, T., Kellermann, T., Ermer, V., Wegener, H. P., Eickhoff, S. B., . . . Shah, N. J. (2010). Electrophysiology meets fMRI: Neural correlates of the startle reflex assessed by simultaneous EMG-fMRI data acquisition. Human Brain Mapping, 31, 16751685.
Okubo, T., & Harada, S. (2001). Polymorphisms of the CCK, CCKAR and CCKBR genes: An association with alcoholism study. Journal of Studies on Alcohol, 62, 413421.
Okubo, T., Harada, S., Higuchi, S., & Matsushita, S. (2002). Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism. Alcoholism, Clinical and Experimental Research, 26, 2S5S.
Owens, D. C., Johnstone, E. C., Miller, P., Macmillan, J. F., & Crow, T. J. (2010). Duration of untreated illness and outcome in schizophrenia: Test of predictions in relation to relapse risk. British Journal of Psychiatry, 196, 296301.
Parker, S. C., Hansen, L., Abaan, H. O., Tullius, T. D., & Margulies, E. H. (2009). Local DNA topography correlates with functional noncoding regions of the human genome. Science, 324, 389392.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., . . . Sham, P. C. (2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559575.
Putnam, L. E., & Roth, W. T. (1990). Effects of stimulus repetition, duration, and rise time on startle blink and automatically elicited P300. Psychophysiology, 27, 275297.
Regier, D. A., Farmer, M. E., Rae, D. S., Locke, B. Z., Keith, S. J., Judd, L. L., . . . Goodwin, F. K. (1990). Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA: Journal of the American Medical Association, 264, 25112518.
Sanjuan, J., Toirac, I., Gonzalez, J. C., Leal, C., Molto, M. D., Najera, C., . . . De Frutos, R. (2004). A possible association between the CCK-AR gene and persistent auditory hallucinations in schizophrenia. European Psychiatry, 19, 349353.
Schall, U., Catts, S. V., Karayanidis, F., & Ward, P. B. (1999). Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: Valid outcome prediction of clozapine therapy in a three-year follow-up. International Journal of Neuropsychopharmacology, 2, 8393.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511, 421427.
Schuckit, M. A., Kelsoe, J. R., Braff, D. L., & Wilhelmsen, K. C. (2003). Some possible genetic parallels across alcoholism, bipolar disorder and schizophrenia. Journal of Studies on Alcohol, 64, 157159.
Shlik, J., Zhou, Y., Koszycki, D., Vaccarino, F. J., & Bradwejn, J. (1999). Effects of CCK-4 infusion on the acoustic eye-blink startle and psychophysiological measures in healthy volunteers. Journal of Psychopharmacology, 13, 385390.
Swerdlow, N. R., Braff, D. L., Taaid, N., & Geyer, M. A. (1994). Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Archives of General Psychiatry, 51, 139154.
Swerdlow, N. R., Caine, S. B., Braff, D. L., & Geyer, M. A. (1992). The neural substrates of sensorimotor gating of the startle reflex: A review of recent findings and their implications. Journal of Psychopharmacology, 6, 176190.
Swerdlow, N. R., & Geyer, M. A. (1999). Neurophysiology and neuropharmacology of short lead interval startle modification. In Dawson, M. E., Schell, A. M. & Bohmelt, A. H. (Eds.), Startle modification: Implications for neuroscience, cognitive science, and clinical science (pp. 114133). Cambridge, UK: Cambridge University Press.
Swerdlow, N. R., Light, G. A., Sprock, J., Calkins, M. E., Green, M. F., Greenwood, T. A., . . . Braff, D. L. (2014). Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS. Schizophrenia Research, 152, 503512.
Takimoto, T., Terayama, H., Waga, C., Okayama, T., Ikeda, K., Fukunishi, I., . . . Iwahashi, K. (2005). Cholecystokinin (CCK) and the CCKA receptor gene polymorphism, and smoking behavior. Psychiatry Research, 133, 123128.
van der Plas, E. A., Crone, E. A., van den Wildenberg, W. P., Tranel, D., & Bechara, A. (2009). Executive control deficits in substance-dependent individuals: A comparison of alcohol, cocaine, and methamphetamine and of men and women. Journal of Clinical and Experimental Neuropsychology, 31, 706719.
Vanakoski, J., Virkkunen, M., Naukkarinen, H., & Goldman, D. (2001). No association of CCK and CCK(B) receptor polymorphisms with alcohol dependence. Psychiatry Research, 102, 17.
Wilson, J., Markie, D., & Fitches, A. (2012). Cholecystokinin system genes: Associations with panic and other psychiatric disorders. Journal of Affective Disorders, 136, 902908.
Yen, C. F., Cheng, C. P., Huang, C. F., Ko, C. H., Yen, J. Y., Chang, Y. P., . . . Chen, C. S. (2009). Relationship between psychosocial adjustment and executive function in patients with bipolar disorder and schizophrenia in remission: The mediating and moderating effects of insight. Bipolar Disorders, 11, 190197.
Zimmerman, M. E., DelBello, M. P., Getz, G. E., Shear, P. K., & Strakowski, S. M. (2006). Anterior cingulate subregion volumes and executive function in bipolar disorder. Bipolar Disorders, 8, 522522.
Zorko, M., Marusic, A., Cebasek-Travnik, Z., & Bucik, V. (2004). The frontal lobe hypothesis: Impairment of executive cognitive functions in chronic alcohol in-patients. Psychiatria Danubina, 16, 2128.


Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort

  • Trina M. Norden-Krichmar (a1) (a2), Ian R. Gizer (a3), Evelyn Phillips (a1), Kirk C. Wilhelmsen (a4), Nicholas J. Schork (a5) and Cindy L. Ehlers (a1)...


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