Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Trends and Directions in Personality Genetic Studies

  • Kim, Han-Na (Department of Biochemistry, School of Medicine, Ewha Womans University) ;
  • Kim, Hyung-Lae (Department of Biochemistry, School of Medicine, Ewha Womans University)
  • Accepted : 2011.06.01
  • Published : 2011.06.30
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Abstract

How personality forms and whether personality genes exist are long-studied questions. Various concepts and theories have been presented for centuries. Personality is a complex trait and is developed through the interaction of genes and the environment. Twin and family studies have found that there are critical genetic and environmental components in the inheritance of personality traits, and modern advances in genetics are making it possible to identify specific variants for personality traits. Although genes that were found in studies on personality have not provided replicable association between genetic and personality variability, more and more genetic variants associated with personality traits are being discovered. Here, we present the current state of the art on genetic research in the personality field and finally list several of the recently published research highlights. First, we briefly describe the commonly used self-reported measures that define personality traits. Then, we summarize the characteristics of the candidate genes for personality traits and investigate gene variants that have been suggested to be associated with personality traits.

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References

  1. Alfimova, M.V., Monakhov, M.V., Golimbet, V.E., Korovaitseva, G.I., and Lyashenko, G.L. (2010). Analysis of associations between 5-HTT, 5-HTR2A, and GABRA6 gene polymorphisms and health-associated personality traits. Bull. Exp. Biol. Med. 149, 434-436. https://doi.org/10.1007/s10517-010-0964-6
  2. Benjamin, J., Li, L., Patterson, C., Greenberg, B.D., Murphy, D.L., and Hamer, D.H. (1996). Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat. Genet. 12, 81-84. https://doi.org/10.1038/ng0196-81
  3. Boomsma, D.I., Beem, A.L., van den Berg, M., Dolan, C.V., Koopmans, J.R., Vink, J.M., de Geus, E.J., and Slagboom, P.E. (2000). Netherlands twin family study of anxious depression (NETSAD). Twin. Res. 3, 323-334. https://doi.org/10.1375/136905200320565300
  4. Bouchard, T.J., Jr., and Loehlin, J.C. (2001). Genes, evolution, and personality. Behav. Genet. 31, 243-273. https://doi.org/10.1023/A:1012294324713
  5. Calboli, F.C., Tozzi, F., Galwey, N.W., Antoniades, A., Mooser, V., Preisig, M., Vollenweider, P., Waterworth, D., Waeber, G., Johnson, M.R., Muglia, P., and Balding, D.J. (2010). A genome-wide association study of neuroticism in a population-based sample. PLoS One 5, e11504. https://doi.org/10.1371/journal.pone.0011504
  6. Cattell, R., Eber, H., and Tatsuoka, M. (1970). Handbook for the Sixteen Personality Factor Questionnaire (16PF) in Clinical, Educational, Industrial, and Research Psychology. (IL: Institute for Personality and Ability Testing: Campaign).
  7. Cloninger, C.R. (1986). A unified biosocial theory of personality and its role in the development of anxiety states. Psychiatr. Dev. 4, 167-226.
  8. Cloninger, C.R. (1987). A systematic method for clinical description and classification of personality variants. A proposal. Arch. Gen. Psychiatry 44, 573-588. https://doi.org/10.1001/archpsyc.1987.01800180093014
  9. Cloninger, C.R., Svrakic, D.M., and Przybeck, T.R. (1993). A psychobiological model of temperament and character. Arch. Gen. Psychiatry 50, 975-990. https://doi.org/10.1001/archpsyc.1993.01820240059008
  10. Cloninger, C.R., Adolfsson, R., and Svrakic, N.M. (1996). Mapping genes for human personality. Nat. Genet. 12, 3-4. https://doi.org/10.1038/ng0196-3
  11. Cloninger, C.R., Van Eerdewegh, P., Goate, A., Edenberg, H.J., Blangero, J., Hesselbrock, V., Reich, T., Nurnberger, J., Jr., Schuckit, M., Porjesz, B., Crowe, R., Rice, J.P., Foroud, T., Przybeck, T.R., Almasy, L., Bucholz, K., Wu, W., Shears, S., Carr, K., Crose, C., Willig, C., Zhao, J., Tischfield, J.A., Li, T.K., Conneally, P.M., and Begleiter, H. (1998). Anxiety proneness linked to epistatic loci in genome scan of human personality traits. Am. J. Med. Genet. 81, 313-317. https://doi.org/10.1002/(SICI)1096-8628(19980710)81:4<313::AID-AJMG7>3.0.CO;2-U
  12. Costa, P., and McCrae, R. (1992). Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) Professional Manual. (Odessa, FL: Psychological Assessment Resources).
  13. Costa, P.T., Jr., and McCrae, R.R. (1997). Stability and change in personality assessment: the revised NEO Personality Inventory in the year 2000. J. Pers. Assess. 68, 86-94. https://doi.org/10.1207/s15327752jpa6801_7
  14. De Fruyt, F., De Wiele, L.V., and Van Heeringen, C. (2000). Cloninger's psychobiological model of temperament and character and the Five-Factor Model of personality. Pers. Individ. Dif. 29, 441-452. https://doi.org/10.1016/S0191-8869(99)00204-4
  15. de Moor, M.H., Costa, P.T., Terracciano, A., Krueger, R.F., de Geus, E.J., Toshiko, T., Penninx, B.W., Esko, T., Madden, P.A., Derringer, J., Amin, N., Willemsen, G., Hottenga, J.J., Distel, M.A., Uda, M., Sanna, S., Spinhoven, P., Hartman, C.A., Sullivan, P., Realo, A., Allik, J., Heath, A.C., Pergadia, M.L., Agrawal, A., Lin, P., Grucza, R., Nutile, T., Ciullo, M., Rujescu, D., Giegling, I., Konte, B., Widen, E., Cousminer, D.L., Eriksson, J.G., Palotie, A., Peltonen, L., Luciano, M., Tenesa, A., Davies, G., Lopez, L.M., Hansell, N.K., Medland, S.E., Ferrucci, L., Schlessinger, D., Montgomery, G.W., Wright, M.J., Aulchenko, Y.S., Janssens, A.C., Oostra, B.A., Metspalu, A., Abecasis, G.R., Deary, I.J., Raikkonen, K., Bierut, L.J., Martin, N.G., van Duijn, C.M., and Boomsma, D.I. (2011). Meta-analysis of genome-wide association studies for personality. Mol. Psychiatry [Epub ahead of print].
  16. De Raad, B. (2000). The big five personality factors: the psycholexical approach to personality (Seattle: Hogrefe and Huber).
  17. Deary, I.J., Battersby, S., Whiteman, M.C., Connor, J.M., Fowkes, F.G., and Harmar, A. (1999). Neuroticism and polymorphisms in the serotonin transporter gene. Psychol. Med. 29, 735-739. https://doi.org/10.1017/S0033291798007557
  18. Ebstein, R.P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., Bennett, E.R., Nemanov, L., Katz, M., and Belmaker, R.H. (1996). Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat. Genet. 12, 78-80. https://doi.org/10.1038/ng0196-78
  19. Ebstein, R.P., Gritsenko, I., Nemanov, L., Frisch, A., Osher, Y., and Belmaker, R.H. (1997a). No association between the serotonin transporter gene regulatory region polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament of harm avoidance. Mol. Psychiatry 2, 224-226. https://doi.org/10.1038/sj.mp.4000275
  20. Ebstein, R.P., Segman, R., Benjamin, J., Osher, Y., Nemanov, L., and Belmaker, R.H. (1997b). 5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms. Am. J. Med. Genet. 74, 65-72. https://doi.org/10.1002/(SICI)1096-8628(19970221)74:1<65::AID-AJMG15>3.0.CO;2-P
  21. Eysenck, H., and Eysenck, S. (1975). Manual of the Eysenck Personality Questionnaire (London: Hodder and Stoughton).
  22. Eysenck, H.J. (1967). The biological basis of personality (Thomas, IL).
  23. Flory, J.D., Manuck, S.B., Ferrell, R.E., Dent, K.M., Peters, D.G., and Muldoon, M.F. (1999). Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol. Psychiatry 4, 93-96. https://doi.org/10.1038/sj.mp.4000466
  24. Frayling, T.M. (2007). Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat. Rev. Genet. 8, 657-662.
  25. Fullerton, J., Cubin, M., Tiwari, H., Wang, C., Bomhra, A., Davidson, S., Miller, S., Fairburn, C., Goodwin, G., Neale, M.C., Fiddy, S., Mott, R., Allison, D.B., and Flint, J. (2003). Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am. J. Hum. Genet. 72, 879-890. https://doi.org/10.1086/374178
  26. Gelernter, J., Kranzler, H., Coccaro, E., Siever, L., New, A., and Mulgrew, C.L. (1997). D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects. Am. J. Hum. Genet. 61, 1144-1152. https://doi.org/10.1086/301595
  27. Gelernter, J., Kranzler, H., Coccaro, E.F., Siever, L.J., and New, A.S. (1998). Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects. Am. J. Psychiatry 155, 1332-1338. https://doi.org/10.1176/ajp.155.10.1332
  28. Gillespie, N.A., Zhu, G., Evans, D.M., Medland, S.E., Wright, M.J., and Martin, N.G. (2008). A genome-wide scan for Eysenckian personality dimensions in adolescent twin sibships: psychoticism, extraversion, neuroticism, and lie. J. Pers. 76, 1415-1446.
  29. Girault, J.A., and Greengard, P. (2004). The neurobiology of dopamine signaling. Arch. Neurol. 61, 641-644. https://doi.org/10.1001/archneur.61.5.641
  30. Goldman, D. (1996). High anxiety. Science 274, 1483. https://doi.org/10.1126/science.274.5292.1483
  31. Greenberg, B.D., Li, Q., Lucas, F.R., Hu, S., Sirota, L.A., Benjamin, J., Lesch, K.P., Hamer, D., and Murphy, D.L. (2000). Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am. J. Med. Genet. 96, 202-216. https://doi.org/10.1002/(SICI)1096-8628(20000403)96:2<202::AID-AJMG16>3.0.CO;2-J
  32. Gustavsson, J.P., Nothen, M.M., Jonsson, E.G., Neidt, H., Forslund, K., Rylander, G., Mattila-Evenden, M., Sedvall, G.C., Propping, P., and Asberg, M. (1999). No association between serotonin transporter gene polymorphisms and personality traits. Am. J. Med. Genet. 88, 430-436. https://doi.org/10.1002/(SICI)1096-8628(19990820)88:4<430::AID-AJMG23>3.0.CO;2-1
  33. Hariri, A.R., Mattay, V.S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., Egan, M.F., and Weinberger, D.R. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400-403. https://doi.org/10.1126/science.1071829
  34. Hettema, J.M., van den Oord, E.J., An, S.S., Kendler, K.S., and Chen, X. (2009). Follow-up association study of novel neuroticism gene MAMDC1. Psychiatr. Genet. 19, 213-214. https://doi.org/10.1097/YPG.0b013e32832cec22
  35. Huang, S.Y., Lin, W.W., Wan, F.J., Chang, A.J., Ko, H.C., Wang, T.J., Wu, P.L., and Lu, R.B. (2007). Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence. J. Psychiatry. Neurosci. 32, 185-192.
  36. Jorm, A.F., Henderson, A.S., Jacomb, P.A., Christensen, H., Korten, A.E., Rodgers, B., Tan, X., and Easteal, S. (2000). Association of a functional polymorphism of the monoamine oxidase A gene promoter with personality and psychiatric symptoms. Psychiatr. Genet. 10, 87-90. https://doi.org/10.1097/00041444-200010020-00006
  37. Katsuragi, S., Kunugi, H., Sano, A., Tsutsumi, T., Isogawa, K., Nanko, S., and Akiyoshi, J. (1999). Association between serotonin transporter gene polymorphism and anxiety-related traits. Biol. Psychiatry 45, 368-370. https://doi.org/10.1016/S0006-3223(98)00090-0
  38. Khan, A.A., Jacobson, K.C., Gardner, C.O., Prescott, C.A., and Kendler, K.S. (2005). Personality and comorbidity of common psychiatric disorders. Br. J. Psychiatry 186, 190-196. https://doi.org/10.1192/bjp.186.3.190
  39. Kirk, K.M., Birley, A.J., Statham, D.J., Haddon, B., Lake, R.I., Andrews, J.G., and Martin, N.G. (2000). Anxiety and depression in twin and sib pairs extremely discordant and concordant for neuroticism: prodromus to a linkage study. Twin. Res. 3, 299-309. https://doi.org/10.1375/136905200320565274
  40. Kuo, P.H., Neale, M.C., Riley, B.P., Patterson, D.G., Walsh, D., Prescott, C.A., and Kendler, K.S. (2007). A genome-wide linkage analysis for the personality trait neuroticism in the Irish affected sib-pair study of alcohol dependence. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 144B, 463-468. https://doi.org/10.1002/ajmg.b.30478
  41. Lee, B.C., Yang, J.W., Lee, S.H., Kim, S.H., Joe, S.H., Jung, I.K., Choi, I.G., and Ham, B.J. (2008). An interaction between the norepinephrine transporter and monoamine oxidase A polymorphisms, and novelty-seeking personality traits in Korean females. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 238-242. https://doi.org/10.1016/j.pnpbp.2007.08.014
  42. Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D., Petri, S., Benjamin, J., Muller, C.R., Hamer, D.H., and Murphy, D.L. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527-1531. https://doi.org/10.1126/science.274.5292.1527
  43. Lin, S.C., Wu, P.L., Ko, H.C., Wu, J.Y., Huang, S.Y., Lin, W.W., and Lu, R.B. (2007). Specific personality traits and dopamine, serotonin genes in anxiety-depressive alcoholism among Han Chinese in Taiwan. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1526-1534. https://doi.org/10.1016/j.pnpbp.2007.07.012
  44. Martin, N., Goodwin, G., Fairburn, C., Wilson, R., Allison, D., Cardon, L.R., and Flint, J. (2000). A population-based study of personality in 34,000 sib-pairs. Twin. Res. 3, 310-315. https://doi.org/10.1375/136905200320565283
  45. Matthews, G., Deary, I.J., and Whiteman, M.C. (2009). Personality Traits , 3rd ed. (Cambridge: Cambridge University Press).
  46. McCrae, R.R., and Terracciano, A. (2005). Universal features of personality traits from the observer's perspective: data from 50 cultures. J. Pers. Soc. Psychol. 88, 547-561. https://doi.org/10.1037/0022-3514.88.3.547
  47. Murakami, F., Shimomura, T., Kotani, K., Ikawa, S., Nanba, E., and Adachi, K. (1999). Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese. J. Hum. Genet. 44, 15-17. https://doi.org/10.1007/s100380050098
  48. Nery, F.G., Hatch, J.P., Nicoletti, M.A., Monkul, E.S., Najt, P., Matsuo, K., Cloninger, C.R., and Soares, J.C. (2009). Temperament and character traits in major depressive disorder: influence of mood state and recurrence of episodes. Depress. Anxiety 26, 382-388. https://doi.org/10.1002/da.20478
  49. Ongur, D., Farabaugh, A., Iosifescu, D.V., Perlis, R., and Fava, M. (2005). Tridimensional personality questionnaire factors in major depressive disorder: relationship to anxiety disorder comorbidity and age of onset. Psychother. Psychosom. 74, 173-178. https://doi.org/10.1159/000084002
  50. Sander, T., Harms, H., Dufeu, P., Kuhn, S., Rommelspacher, H., and Schmidt, L.G. (1997). Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics. Am. J. Med. Genet. 74, 483-487. https://doi.org/10.1002/(SICI)1096-8628(19970919)74:5<483::AID-AJMG5>3.0.CO;2-P
  51. Shifman, S., Bhomra, A., Smiley, S., Wray, N.R., James, M.R., Martin, N.G., Hettema, J.M., An, S.S., Neale, M.C., van den Oord, E.J., Kendler, K.S., Chen, X., Boomsma, D.I., Middeldorp, C.M., Hottenga, J.J., Slagboom, P.E., and Flint, J. (2008). A whole genome association study of neuroticism using DNA pooling. Mol. Psychiatry 13, 302-312. https://doi.org/10.1038/sj.mp.4002048
  52. Soliman, A., Bagby, R.M., Wilson, A.A., Miler, L., Clark, M., Rusjan, P., Sacher, J., Houle, S., and Meyer, J.H. (2011). Relationship of monoamine oxidase A binding to adaptive and maladaptive personality traits. Psychol. Med. 41, 1051-1060. https://doi.org/10.1017/S0033291710001601
  53. Stallings, M.C., Hewitt, J.K., Cloninger, C.R., Heath, A.C., and Eaves, L.J. (1996). Genetic and environmental structure of the Tridimensional Personality Questionnaire: three or four temperament dimensions? J. Pers. Soc. Psychol. 70, 127-140. https://doi.org/10.1037/0022-3514.70.1.127
  54. Sullivan, P.F., Fifield, W.J., Kennedy, M.A., Mulder, R.T., Sellman, J.D., and Joyce, P.R. (1998). No association between novelty seeking and the type 4 dopamine receptor gene (DRD4) in two New Zealand samples. Am. J. Psychiatry 155, 98-101. https://doi.org/10.1176/ajp.155.1.98
  55. Suzuki, A., Matsumoto, Y., Shibuya, N., Sadahiro, R., Kamata, M., Goto, K., and Otani, K. (2011). The brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of parental rearing on personality traits in healthy subjects. Genes. Brain. Behav. 10, 385-391. https://doi.org/10.1111/j.1601-183X.2010.00673.x
  56. Terracciano, A., Martin, B., Ansari, D., Tanaka, T., Ferrucci, L., Maudsley, S., Mattson, M.P., and Costa, P.T., Jr. (2010a). Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits. Genes. Brain. Behav. 9, 512-518.
  57. Terracciano, A., Sanna, S., Uda, M., Deiana, B., Usala, G., Busonero, F., Maschio, A., Scally, M., Patriciu, N., Chen, W.M., Distel, M.A., Slagboom, E.P., Boomsma, D.I., Villafuerte, S., Sliwerska, E., Burmeister, M., Amin, N., Janssens, A.C., van Duijn, C.M., Schlessinger, D., Abecasis, G.R., and Costa, P.T., Jr. (2010b). Genomewide association scan for five major dimensions of personality. Mol. Psychiatry 15, 647-656. https://doi.org/10.1038/mp.2008.113
  58. Tochigi, M., Hibino, H., Otowa, T., Kato, C., Marui, T., Ohtani, T., Umekage, T., Kato, N., and Sasaki, T. (2006). Association between dopamine D4 receptor (DRD4) exon III polymorphism and Neuroticism in the Japanese population. Neurosci. Lett. 398, 333-336. https://doi.org/10.1016/j.neulet.2006.01.020
  59. Tochigi, M., Hibino, H., Otowa, T., Ohtani, T., Ebisawa, T., Kato, N., and Sasaki, T. (2006). No association of 5-HT2C, 5-HT6, and tryptophan hydroxylase-1 gene polymorphisms with personality traits in the Japanese population. Neurosci. Lett. 403, 100-102. https://doi.org/10.1016/j.neulet.2006.04.020
  60. Tochigi, M., Otowa, T., Hibino, H., Kato, C., Otani, T., Umekage, T., Utsumi, T., Kato, N., and Sasaki, T. (2006). Combined analysis of association between personality traits and three functional polymorphisms in the tyrosine hydroxylase, monoamine oxidase A, and catechol-Omethyltransferase genes. Neurosci. Res. 54, 180-185. https://doi.org/10.1016/j.neures.2005.11.003
  61. Tsai, S.J., Hong, C.J., and Cheng, C.Y. (2002). Serotonin transporter genetic polymorphisms and harm avoidance in the Chinese. Psychiatr. Genet. 12, 165-168. https://doi.org/10.1097/00041444-200209000-00008
  62. Tsuchimine, S., Yasui-Furukori, N., Kaneda, A., Saito, M., Sugawara, N., and Kaneko, S. (2009). Minor genetic variants of the dopamine D4 receptor (DRD4) polymorphism are associated with novelty seeking in healthy Japanese subjects. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 1232-1235.
  63. Urata, T., Takahashi, N., Hakamata, Y., Iijima, Y., Kuwahara, N., Ozaki, N., Ono, Y., Amano, M., and Inada, T. (2007). Gene-gene interaction analysis of personality traits in a Japanese population using an electrochemical DNA array chip analysis. Neurosci. Lett. 414, 209-212. https://doi.org/10.1016/j.neulet.2006.12.018
  64. van den Oord, E.J., Kuo, P.H., Hartmann, A.M., Webb, B.T., Moller, H.J., Hettema, J.M., Giegling, I., Bukszar, J., and Rujescu, D. (2008). Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Arch. Gen. Psychiatry 65, 1062-1071. https://doi.org/10.1001/archpsyc.65.9.1062
  65. Van Gestel, S., and Van Broeckhoven, C. (2003). Genetics of personality: are we making progress? Mol. Psychiatry 8, 840-852. https://doi.org/10.1038/sj.mp.4001367
  66. Verweij, K.J., Zietsch, B.P., Medland, S.E., Gordon, S.D., Benyamin, B., Nyholt, D.R., McEvoy, B.P., Sullivan, P.F., Heath, A.C., Madden, P.A., Henders, A.K., Montgomery, G.W., Martin, N.G., and Wray, N.R. (2010). A genome-wide association study of Cloninger's temperament scales: implications for the evolutionary genetics of personality. Biol. Psychol. 85, 306-317. https://doi.org/10.1016/j.biopsycho.2010.07.018
  67. Visscher, P.M. (2008). Sizing up human height variation. Nat. Genet. 40, 489-490. https://doi.org/10.1038/ng0508-489
  68. Zohar, A.H., Dina, C., Rosolio, N., Osher, Y., Gritsenko, I., Bachner-Melman, R., Benjamin, J., Belmaker, R.H., and Ebstein, R.P. (2003). Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 117B, 66-69. https://doi.org/10.1002/ajmg.b.10029

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