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Direct, indirect and pleiotropic effects of candidate genes on internalizing disorder psychopathology

Published online by Cambridge University Press:  23 February 2015

J. M. Hettema ,
X. Chen ,
C. Sun  and
T. A. Brown
J. M. Hettema*
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
X. Chen
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
C. Sun
Affiliation:
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
T. A. Brown
Affiliation:
Department of Psychology, Center for Anxiety and Related Disorders, Boston University, Boston, MA, USA
*
*Address for correspondence: J. M. Hettema, VCU Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, PO Box 980126, Richmond, VA 23298-0126, USA. (Email: [email protected])
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Abstract

Background

Twin studies of internalizing disorders suggest that their high co-morbidity is partially explained by shared genetic risk. Few studies have investigated pleiotropic effects of well-validated candidate genes across phenotypes.

Method

Subjects were 928 Caucasian patients who presented to an out-patient clinic specializing in the assessment and treatment of anxiety and mood disorders. We constructed latent dimensional phenotypes across the internalizing spectrum (neuroticism, extraversion, depression, generalized anxiety, panic/agoraphobia, social phobia, post-traumatic stress, and obsessions–compulsions) by combining diagnostic criteria with other clinical indicators. We selected multiple variants in four evidence-based candidate genes (SLC6A4, COMT, GAD1, RGS2) with previously reported effects on several of these phenotypes. We conducted genetic association testing of their direct and indirect effects as well as gene × stress interactions (G × E).

Results

We detected 19 nominally significant main effect associations for the 10 polymorphisms tested among the eight phenotypes (24%). These were generally phenotype non-specific, showing pleiotropic effects across multiple domains. The majority of observed sharing was between depression, panic disorder, and post-traumatic stress disorder. Some of these were best explained by mediational models in which genes increase liability for disorders indirectly via their effects on temperament. Limited G × E effects were detected between variants in SLC6A4 and both panic/agoraphobia and post-traumatic stress.

Conclusions

Examining just a few candidate genes for their potential roles in internalizing phenotypes, we found moderate support for the shared effects of several polymorphisms. These findings highlight the richness and complexity by which genes potentially contribute to psychopathology via pleiotropy, moderation by stress, and mediation by temperament.

Keywords

Anxiety disordercandidate genesdepressiongenetic associationsstructural equation modelingtemperament
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 10 , July 2015 , pp. 2227 - 2236
Copyright
Copyright © Cambridge University Press 2015 

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References

Allison, PD (2003). Missing data techniques for structural equation modeling. Journal of Abnormal Psychology 112, 545–557.CrossRefGoogle ScholarPubMed
Andrews, G, Stewart, G, Morris-Yates, A, Holt, P, Henderson, S (1990). Evidence for a general neurotic syndrome. British Journal of Psychiatry 157, 6–12.Google Scholar
Antony, MM, Bieling, PJ, Cox, BJ, Enns, MW, Swinson, RP (1998). Psychometric properties of the 42-item and 21-item versions of the Depression Anxiety Stress Scales in clinical groups and a community sample. Psychological Assessment 10, 176–181.Google Scholar
Barrett, JC, Fry, B, Maller, J, Daly, MJ (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265.CrossRefGoogle ScholarPubMed
Beck, AT, Steer, RA, Brown, GK (1996). Manual for the Beck Depression Inventory-II. Psychological Corporation: San Antonio.Google Scholar
Bienvenu, OJ, Brown, C, Samuels, JF, Liang, KY, Costa, PT, Eaton, WW, Nestadt, G (2001). Normal personality traits and comorbidity among phobic, panic and major depressive disorders. Psychiatry Research 102, 73–85.Google Scholar
Bienvenu, OJ, Hettema, J, Neale, MC, Prescott, CA, Kendler, KS (2007). Low extraversion and high neuroticism as indices of genetic and environmental risk for social phobia. American Journal of Psychiatry 164, 1714–1721.CrossRefGoogle ScholarPubMed
Bienvenu, OJ, Samuels, JF, Wuyek, LA, Liang, KY, Wang, Y, Grados, MA, Cullen, BA, Riddle, MA, Greenberg, BD, Rasmussen, SA, Fyer, AJ, Pinto, A, Rauch, SL, Pauls, DL, McCracken, JT, Piacentini, J, Murphy, DL, Knowles, JA, Nestadt, G (2012). Is obsessive–compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective. Psychological Medicine 42, 1–13.CrossRefGoogle ScholarPubMed
Bloch, MH, Landeros-Weisenberger, A, Sen, S, Dombrowski, P, Kelmendi, B, Coric, V, Pittenger, C, Leckman, JF (2008). Association of the serotonin transporter polymorphism and obsessive–compulsive disorder: systematic review. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147B, 850–858.Google Scholar
Brown, TA (2007). Temporal course and structural relationships among dimensions of temperament and DSM-IV anxiety and mood disorder constructs. Journal of Abnormal Psychology 116, 313–328.Google Scholar
Brown, TA, Di Nardo, PA, Lehman, CL, Campbell, LA (2001). Reliability of DSM-IV anxiety and mood disorders: implications for the classification of emotional disorders. Journal of Abnormal Psychology 110, 49–58.Google Scholar
Brown, TA, Naragon-Gainey, K (2013). Evaluation of the unique and specific contributions of dimensions of the triple vulnerability model to the prediction of DSM-IV anxiety and mood disorder constructs. Behavior Therapy 44, 277–292.CrossRefGoogle Scholar
Brown, TA, Rosellini, AJ (2011). The direct and interactive effects of neuroticism and life stress on the severity and longitudinal course of depressive symptoms. Journal of Abnormal Psychology 120, 844–856.CrossRefGoogle ScholarPubMed
Brown, TA, White, KS, Barlow, DH (2005). A psychometric reanalysis of the Albany Panic and Phobia Questionnaire. Behaviour Research and Therapy 43, 337–355.Google Scholar
Carver, CS, White, TL (1994). Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS scales. Journal of Personality and Social Psychology 67, 319–333.Google Scholar
Costa, PT Jr, McCrae, RR (1992). Revised NEO Personality Inventory (NEO PI-R) and NEO Five-Factor Inventory (NEO-FFI) Professional Manual. Psychological Assessment Resources: Odessa, FL.Google Scholar
Craddock, N, Owen, MJ, O'Donovan, MC (2006). The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Molecular Psychiatry 11, 446–458.CrossRefGoogle ScholarPubMed
Cross-Disorder Group of the Psychiatric GWAS Consortium (2013). Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379.CrossRefGoogle Scholar
de Moor, MH, Costa, PT, Terracciano, A, Krueger, RF, de Geus, EJ, Toshiko, T, Penninx, BW, Esko, T, Madden, PA, Derringer, J, Amin, N, Willemsen, G, Hottenga, JJ, Distel, MA, Uda, M, Sanna, S, Spinhoven, P, Hartman, CA, Sullivan, P, Realo, A, Allik, J, Heath, AC, Pergadia, ML, Agrawal, A, Lin, P, Grucza, R, Nutile, T, Ciullo, M, Rujescu, D, Giegling, I, Konte, B, Widen, E, Cousminer, DL, Eriksson, JG, Palotie, A, Peltonen, L, Luciano, M, Tenesa, A, Davies, G, Lopez, LM, Hansell, NK, Medland, SE, Ferrucci, L, Schlessinger, D, Montgomery, GW, Wright, MJ, Aulchenko, YS, Janssens, AC, Oostra, BA, Metspalu, A, Abecasis, GR, Deary, IJ, Raikkonen, K, Bierut, LJ, Martin, NG, van Duijn, CM, Boomsma, DI (2012). Meta-analysis of genome-wide association studies for personality. Molecular Psychiatry 17, 337–349.Google Scholar
Di Nardo, PA, Brown, TA, Barlow, DH (1994). Anxiety Disorders Interview Schedule for DSM-IV: Lifetime Version (ADIS-IV-L). Oxford University Press: New York.Google Scholar
Digangi, J, Guffanti, G, McLaughlin, KA, Koenen, KC (2013). Considering trauma exposure in the context of genetics studies of posttraumatic stress disorder: a systematic review. Biology of Mood and Anxiety Disorders 3, 2.Google Scholar
Domschke, K, Deckert, J, O'Donovan, MC, Glatt, SJ (2007). Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 144B, 667–673.CrossRefGoogle ScholarPubMed
Donner, J, Sipila, T, Ripatti, S, Kananen, L, Chen, X, Kendler, KS, Lonnqvist, J, Pirkola, S, Hettema, JM, Hovatta, I (2012). Support for involvement of glutamate decarboxylase 1 and neuropeptide Y in anxiety susceptibility. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 159B, 316–327.Google Scholar
Erhardt, A, Czibere, L, Roeske, D, Lucae, S, Unschuld, PG, Ripke, S, Specht, M, Kohli, MA, Kloiber, S, Ising, M, Heck, A, Pfister, H, Zimmermann, P, Lieb, R, Putz, B, Uhr, M, Weber, P, Deussing, JM, Gonik, M, Bunck, M, Kebler, MS, Frank, E, Hohoff, C, Domschke, K, Krakowitzky, P, Maier, W, Bandelow, B, Jacob, C, Deckert, J, Schreiber, S, Strohmaier, J, Nothen, M, Cichon, S, Rietschel, M, Bettecken, T, Keck, ME, Landgraf, R, Muller-Myhsok, B, Holsboer, F, Binder, EB (2011). TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies. Molecular Psychiatry 16, 647–663.CrossRefGoogle ScholarPubMed
Eysenck, HJ, Eysenck, SBG (1975). Manual of the Eysenck Personality Questionnaire. Hodder and Stoughton: London.Google Scholar
Foa, EB, Huppert, JD, Leiberg, S, Langner, R, Kichic, R, Hajcak, G, Salkovskis, PM (2002). The Obsessive-Compulsive Inventory: development and validation of a short version. Psychological Assessment 14, 485–496.Google Scholar
Gyawali, S, Subaran, R, Weissman, MM, Hershkowitz, D, McKenna, MC, Talati, A, Fyer, AJ, Wickramaratne, P, Adams, PB, Hodge, SE, Schmidt, CJ, Bannon, MJ, Glatt, CE (2010). Association of a polyadenylation polymorphism in the serotonin transporter and panic disorder. Biological Psychiatry 67, 331–338.CrossRefGoogle ScholarPubMed
Hammen, C, Adrian, C, Gordon, D, Burge, D, Jaenicke, C, Hiroto, D (1987). Children of depressed mothers: maternal strain and symptom predictors of dysfunction. Journal of Abnormal Psychology 96, 190–198.Google Scholar
Hettema, JM, An, SS, Bukszar, J, van den Oord, EJ, Neale, MC, Kendler, KS, Chen, X (2008). Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes. Biological Psychiatry 64, 302–310.Google Scholar
Hettema, JM, An, SS, Neale, MC, Bukszar, J, van den Oord, EJ, Kendler, KS, Chen, X (2006 a). Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Molecular Psychiatry 11, 752–762.Google Scholar
Hettema, JM, Neale, MC, Kendler, KS (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. American Journal of Psychiatry 158, 1568–1578.Google Scholar
Hettema, JM, Neale, MC, Myers, JM, Prescott, CA, Kendler, KS (2006 b). A population-based twin study of the relationship between neuroticism and internalizing disorders. American Journal of Psychiatry 163, 857–864.Google Scholar
Hettema, JM, Sun, C, Chen, X, Kendler, KS (2013). Genetic association study between RGS2 and anxiety-related phenotypes. Psychiatric Genetics 23, 92.Google Scholar
Hu, L, Bentler, PM (1999). Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Structural Equation Modeling 6, 1–55.CrossRefGoogle Scholar
Jardine, R, Martin, NG, Henderson, AS (1984). Genetic covariation between neuroticism and the symptoms of anxiety and depression. Genetic Epidemiology 1, 89–107.Google Scholar
Kendler, KS, Gardner, CO, Gatz, M, Pedersen, NL (2007). The sources of co-morbidity between major depression and generalized anxiety disorder in a Swedish national twin sample. Psychological Medicine 37, 453–462.CrossRefGoogle Scholar
Kendler, KS, Neale, MC, Kessler, RC, Heath, AC, Eaves, LJ (1993). A longitudinal twin study of personality and major depression in women. Archives of General Psychiatry 50, 853–862.Google Scholar
Kessler, RC, Berglund, P, Demler, O, Jin, R, Merikangas, KR, Walters, EE (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 593–602.Google Scholar
Khan, AA, Jacobson, KC, Gardner, CO, Prescott, CA, Kendler, KS (2005). Personality and comorbidity of common psychiatric disorders. British Journal of Psychiatry 186, 190–196.CrossRefGoogle ScholarPubMed
Koenen, KC, Amstadter, AB, Ruggiero, KJ, Acierno, R, Galea, S, Kilpatrick, DG, Gelernter, J (2009). RGS2 and generalized anxiety disorder in an epidemiologic sample of hurricane-exposed adults. Depression and Anxiety 26, 309–315.Google Scholar
Leygraf, A, Hohoff, C, Freitag, C, Willis-Owen, SA, Krakowitzky, P, Fritze, J, Franke, P, Bandelow, B, Fimmers, R, Flint, J, Deckert, J (2006). Rgs 2 gene polymorphisms as modulators of anxiety in humans? Journal of Neural Transmission 113, 1921–1925.Google Scholar
Livak, KJ (1999). Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genetic Analysis 14, 143–149.Google Scholar
Lovibond, PF, Lovibond, SH (1995). The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behaviour Research and Therapy 33, 335–343.Google Scholar
Mandelli, L, Serretti, A (2013). Gene environment interaction studies in depression and suicidal behavior: an update. Neuroscience and Biobehavioral Reviews 37, 2375–2397.Google Scholar
Mattick, RP, Clarke, JC (1998). Development and validation of measures of social phobia scrutiny fear and social interaction anxiety. Behaviour Research and Therapy 36, 455–470.Google Scholar
Meyer, TJ, Miller, ML, Metzger, RL, Borkovec, TD (1990). Development and validation of the Penn State Worry Questionnaire. Behaviour Research and Therapy 28, 487–495.Google Scholar
Monzani, B, Rijsdijk, F, Harris, J, Mataix-Cols, D (2014). The structure of genetic and environmental risk factors for dimensional representations of DSM-5 obsessive–compulsive spectrum disorders. JAMA Psychiatry 71, 182–189.Google Scholar
Munafò, MR, Clark, TG, Roberts, KH, Johnstone, EC (2006). Neuroticism mediates the association of the serotonin transporter gene with lifetime major depression. Neuropsychobiology 53, 1–8.Google Scholar
Muthén, LK, Muthén, BO (2010). Mplus User's Guide. Muthén & Muthén: Los Angeles, CA.Google Scholar
Naragon-Gainey, K, Gallagher, MW, Brown, TA (2013). Stable “trait” variance of temperament as a predictor of the temporal course of depression and social phobia. Journal of Abnormal Psychology 122, 611–623.Google Scholar
Pauls, DL (2010). The genetics of obsessive-compulsive disorder: a review. Dialogues in Clinical Neuroscience 12, 149–163.CrossRefGoogle ScholarPubMed
Pooley, EC, Fineberg, N, Harrison, PJ (2007). The met(158) allele of catechol-O-methyltransferase (COMT) is associated with obsessive–compulsive disorder in men: case–control study and meta-analysis. Molecular Psychiatry 12, 556–561.Google Scholar
Rapee, RM, Craske, MG, Barlow, DH (1994–1995). Assessment instrument for panic disorder that includes fear of sensation-producing activities: the Albany Panic and Phobia Questionnaire. Anxiety 1, 114–122.Google Scholar
Ripke, S, Wray, NR, Lewis, CM, Hamilton, SP, Weissman, MM, Breen, G, Byrne, EM, Blackwood, DH, Boomsma, DI, Cichon, S, Heath, AC, Holsboer, F, Lucae, S, Madden, PA, Martin, NG, McGuffin, P, Muglia, P, Noethen, MM, Penninx, BP, Pergadia, ML, Potash, JB, Rietschel, M, Lin, D, Muller-Myhsok, B, Shi, J, Steinberg, S, Grabe, HJ, Lichtenstein, P, Magnusson, P, Perlis, RH, Preisig, M, Smoller, JW, Stefansson, K, Uher, R, Kutalik, Z, Tansey, KE, Teumer, A, Viktorin, A, Barnes, MR, Bettecken, T, Binder, EB, Breuer, R, Castro, VM, Churchill, SE, Coryell, WH, Craddock, N, Craig, IW, Czamara, D, de Geus, EJ, Degenhardt, F, Farmer, AE, Fava, M, Frank, J, Gainer, VS, Gallagher, PJ, Gordon, SD, Goryachev, S, Gross, M, Guipponi, M, Henders, AK, Herms, S, Hickie, IB, Hoefels, S, Hoogendijk, W, Hottenga, JJ, Iosifescu, DV, Ising, M, Jones, I, Jones, L, Jung-Ying, T, Knowles, JA, Kohane, IS, Kohli, MA, Korszun, A, Landen, M, Lawson, WB, Lewis, G, Macintyre, D, Maier, W, Mattheisen, M, McGrath, PJ, McIntosh, A, McLean, A, Middeldorp, CM, Middleton, L, Montgomery, GM, Murphy, SN, Nauck, M, Nolen, WA, Nyholt, DR, O'Donovan, M, Oskarsson, H, Pedersen, N, Scheftner, WA, Schulz, A, Schulze, TG, Shyn, SI, Sigurdsson, E, Slager, SL, Smit, JH, Stefansson, H, Steffens, M, Thorgeirsson, T, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, EJ, Van, GG, Volzke, H, Weilburg, JB, Willemsen, G, Zitman, FG, Neale, B, Daly, M, Levinson, DF, Sullivan, PF (2013). A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry 18, 497–511.Google Scholar
Risch, N, Herrell, R, Lehner, T, Liang, KY, Eaves, L, Hoh, J, Griem, A, Kovacs, M, Ott, J, Merikangas, KR (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301, 2462–2471.Google Scholar
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.Google Scholar
Simms, LJ, Watson, D, Doebbeling, BN (2002). Confirmatory factor analyses of posttraumatic stress symptoms in deployed and nondeployed veterans of the Gulf War. Journal of Abnormal Psychology 111, 637–647.Google Scholar
Smoller, JW, Paulus, MP, Fagerness, JA, Purcell, S, Yamaki, LH, Hirshfeld-Becker, D, Biederman, J, Rosenbaum, JF, Gelernter, J, Stein, MB (2008). Influence of RGS2 on anxiety-related temperament, personality, and brain function. Archives of General Psychiatry 65, 298–308.Google Scholar
Stein, DJ, Fineberg, NA, Bienvenu, OJ, Denys, D, Lochner, C, Nestadt, G, Leckman, JF, Rauch, SL, Phillips, KA (2010). Should OCD be classified as an anxiety disorder in DSM-V? Depression and Anxiety 27, 495–506.Google Scholar
Strug, LJ, Suresh, R, Fyer, AJ, Talati, A, Adams, PB, Li, W, Hodge, SE, Gilliam, TC, Weissman, MM (2010). Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Molecular Psychiatry 15, 166–176.Google Scholar
Tambs, K, Czajkowsky, N, Roysamb, E, Neale, MC, Reichborn-Kjennerud, T, Aggen, SH, Harris, JR, Orstavik, RE, Kendler, KS (2009). Structure of genetic and environmental risk factors for dimensional representations of DSM-IV anxiety disorders. British Journal of Psychiatry 195, 301–307.Google Scholar
Willis-Owen, SA, Turri, MG, Munafò, MR, Surtees, PG, Wainwright, NW, Brixey, RD, Flint, J (2005). The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biological Psychiatry 58, 451–456.Google Scholar
Wray, NR, James, MR, Gordon, SD, Dumenil, T, Ryan, L, Coventry, WL, Statham, DJ, Pergadia, ML, Madden, PA, Heath, AC, Montgomery, GW, Martin, NG (2009). Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures. Biological Psychiatry 66, 468–476.Google Scholar
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