Abstract
Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.
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References
Arbelle S, Benjamin J, Golin M, Kremer I, Belmaker RH, Ebstein RP (2003). Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism. Am J Psychiatry 160: 671–676.
Bienvenu OJ, Samuels JF, Costa PT, Reti IM, Eaton WW, Nestadt G (2004). Anxiety depressive disorders the five-factor model of personality: a higher- lower-order personality trait investigation in a community sample. Depress Anxiety 20: 92–97.
Bouchard TJ, Loehlin JC (2001). Genes evolution, personality. Behav Genet 31: 243–273.
Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK (2006). BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59: 812–815.
Carvalho AL, Caldeira MV, Santos SD, Duarte CB (2008). Role of the brain-derived neurotrophic factor at glutamatergic synapses. Br J Pharmacol 153 (Suppl 1): S310–S324.
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001). Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50: 260–265.
Chen WM, Abecasis GR (2007). Family-based association tests for genomewide association scans. Am J Hum Genet 81: 913–926.
Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ et al (2006). Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314: 140–143.
Clark LA, Watson D, Mineka S (1994). Temperament, personality, and the mood and anxiety disorders. J Abnorm Psychol 103: 103–116.
Costa Jr PT, McCrae RR (1980). Influence of extraversion neuroticism on subjective well-being: happy unhappy people. J Pers Soc Psychol 38: 668–678.
Costa Jr PT, McCrae RR (1992). Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) Professional Manual. Psychological Assessment Resources: Odessa, FL.
Costa Jr PT, Terracciano A, McCrae RR (2001). Gender differences in personality traits across cultures: robust and surprising findings. J Pers Soc Psychol 81: 322–331.
Costa Jr PT, Terracciano A, Uda M, Vacca L, Mameli C, Pilia G et al (2007). Personality traits in Sardinia: testing founder population effects on trait means and variances. Behav Genet 37: 376–387.
Cotman CW, Berchtold NC (2002). Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25: 295–301.
Devlin B, Roeder K (1999). Genomic control for association studies. Biometrics 55: 997–1004.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112: 257–269.
Frustaci A, Pozzi G, Gianfagna F, Manzoli L, Boccia S (2008). Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits. Neuropsychobiology 58: 163–170.
Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR et al (2009). Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 14: 681–695.
Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X (2007). Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case–control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 61: 911–922.
Green EK, Raybould R, Macgregor S, Hyde S, Young AH, O'Donovan MC et al (2006). Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case–control study of over 3000 individuals from the UK. Br J Psychiatry 188: 21–25.
Gunthert KC, Conner TS, Armeli S, Tennen H, Covault J, Kranzler HR (2007). Serotonin transporter gene polymorphism (5-HTTLPR) and anxiety reactivity in daily life: a daily process approach to gene–environment interaction. Psychosom Med 69: 762–768.
Henningsson S, Borg J, Lundberg J, Bah J, Lindstrom M, Ryding E et al (2009). Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1a receptor availability in men. Biol Psychiatry 66: 477–885.
Hunnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP (2007). Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology 32: 2552–2560.
Itoh K, Hashimoto K, Kumakiri C, Shimizu E, Iyo M (2004). Association between brain-derived neurotrophic factor 196 G/A polymorphism and personality traits in healthy subjects. Am J Med Genet B Neuropsychiatr Genet 124B: 61–63.
Jylha P, Melartin T, Rytsala H, Isometsä E (2009). Neuroticism, introversion, and major depressive disorder—traits, states, or scars? Depress Anxiety 26: 325–334.
Kendler KS, Gatz M, Gardner CO, Pedersen NL (2006). Personality and major depression: a Swedish longitudinal, population-based twin study. Arch Gen Psychiatry 63: 1113–1120.
Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH et al (2007). Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry 62: 423–428.
Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T et al (2005). Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 180: 95–99.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274: 1527–1531.
Mamounas LA, Blue ME, Siuciak JA, Altar CA (1995). Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15: 7929–7939.
Martinowich K, Lu B (2008). Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 33: 73–83.
Matsuo K, Walss-Bass C, Nery FG, Nicoletti MA, Hatch JP, Frey BN et al (2009). Neuronal correlates of brain-derived neurotrophic factor Val66Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology 34: 1904–1913.
Mattson MP, Maudsley S, Martin B (2004). BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27: 589–594.
McCrae RR, Terracciano A, 78 Members of the Personality Profiles of Cultures Project (2005a). Universal features of personality traits from the observer's perspective: data from 50 cultures. J Pers Soc Psychol 88: 547–561.
McCrae RR, Terracciano A, 79 Member of the Personality Profiles of Cultures Project (2005b). Personality profiles of cultures: aggregate personality traits. J Pers Soc Psychol 89: 407–425.
McCrae RR, Terracciano A, De Fruyt F, De Bolle M, Gelfand MJ, Costa PTJ, et al. The validity and structure of culture-level personality scores: data from ratings of young adolescents. J Pers. (in press).
Mossner R, Daniel S, Albert D, Heils A, Okladnova O, Schmitt A, et al (2000). Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem Int 36: 197–202.
Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ et al (2008). Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Mol Psychiatry; e-pub ahead of print 28 December 2008.
Munafo MR, Freimer NB, Ng W, Ophoff R, Veijola J, Miettunen J et al (2008). 5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet 150B: 271–281.
Nibuya M, Morinobu S, Duman RS (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15: 7539–7547.
Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS et al (2008). Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry 13: 709–716.
Pilia G, Chen WM, Scuteri A, Orrú M, Albai G, Dei M et al (2006). Heritability of cardiovascular and personality traits in 6148 Sardinians. PloS Genetics 2: e132.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909.
Rybakowski JK (2008). BDNF gene: functional Val66Met polymorphism in mood disorders and schizophrenia. Pharmacogenomics 9: 1589–1593.
Rybakowski JK, Suwalska A, Skibinska M, Dmitrzak-Weglarz M, Leszczynska-Rodziewicz A, Hauser J (2007). Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes. Am J Med Genet B Neuropsychiatr Genet 144B: 820–823.
Schmitt DP, Allik J, McCrae RR, Benet-Martínez V (2007). The geographic distribution of big five personality traits: patterns and profiles of human self-description across 56 nations. J Cross Cult Psychol 38: 173–212.
Sen S, Duman R, Sanacora G (2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64: 527–532.
Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A et al (2003). A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28: 397–401.
Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM (1996). Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56: 131–137.
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G et al (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry 7: 579–593.
Terracciano A (2003). The Italian version of the NEO PI-R: conceptual and empirical support for the use of targeted rotation. Pers Individ Dif 35: 1859–1872.
Terracciano A, Balaci L, Thayer J, Scally M, Kokinos S, Ferrucci L et al (2009a). Variants of the serotonin transporter gene and NEO-PI-R Neuroticism: no association in the BLSA and SardiNIA samples. Am J Med Genet B Neuropsychiatr Genet 150B: 1070–1077.
Terracciano A, Costa PTJ, McCrae RR (2006). Personality plasticity after age 30. Pers Soc Psychol Bull 32: 999–1009.
Terracciano A, McCrae RR, Brant LJ, Costa Jr PT (2005). Hierarchical linear modeling analyses of NEO-PI-R scales in the Baltimore Longitudinal Study of Aging. Psychol Aging 20: 493–506.
Terracciano A, McCrae RR, Costa Jr PT (in press) Intra-individual change in personality stability and age. J R Pers; doi:10.1016/j.jrp.2009.1009.1006.
Terracciano A, Sanna S, Uda M, Deiana B, Usala G, Busonero F et al (2008). Genome-wide association scan for five major dimensions of personality. Mol Psychiatry; e-pub ahead of print 28 October 2008, doi: 10.1038/mp.2008.1113.
Terracciano A, Sutin AR, McCrae RR, Deiana B, Ferrucci L, Schlessinger D et al (2009b). Facets of personality linked to underweight and overweight. Psychosom Med 71: 682–689.
Tochigi M, Otowa T, Suga M, Rogers M, Minato T, Yamasue H et al (2006). No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits. Schizophr Res 87: 45–47.
van den Oord EJCG, Kuo P-H, Hartmann AM, Webb BT, Moller H-J, Hettema JM et al (2008). Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Arch Gen Psychiatry 65: 1062–1071.
Wachleski C, Blaya C, Salum GA, Vargas V, Leistner-Segal S, Manfro GG (2008). Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder. Neurosci Lett 431: 173–178.
Watson D, Clark LA (1992). On traits and temperament: general and specific factors of emotional experience and their relation to the five-factor model. J Pers 60: 441–476.
Watson D, Gamez W, Simms LJ (2005). Basic dimensions of temperament and their relation to anxiety and depression: a symptom-based perspective. J Res Pers 39: 46–66.
Wendland JR, Kruse MR, Cromer KR, Murphy DL (2007). A large case–control study of common functional SLC6A4 and BDNF variants in obsessive-compulsive disorder. Neuropsychopharmacology 32: 2543–2551.
Wichers M, Kenis G, Jacobs N, Mengelers R, Derom C, Vlietinck R et al (2008). The BDNF Val(66)Met × 5-HTTLPR × child adversity interaction and depressive symptoms: an attempt at replication. Am J Med Genet B Neuropsychiatr Genet 147B: 120–123.
Willis-Owen SA, Fullerton J, Surtees PG, Wainwright NW, Miller S, Flint J (2005a). The Val66Met coding variant of the brain-derived neurotrophic factor (BDNF) gene does not contribute toward variation in the personality trait neuroticism. Biol Psychiatry 58: 738–742.
Willis-Owen SA, Turri MG, Munafo MR, Surtees PG, Wainwright NW, Brixey RD et al (2005b). The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry 58: 451–456.
Wray NR, James MR, Gordon SD, Dumenil T, Ryan L, Coventry WL et al (2009). Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures. Biol Psychiatry 66: 468–476.
Wray NR, James MR, Handoko HY, Dumenil T, Lind PA, Montgomery GW et al (2008). Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression. Psychiatr Genet 18: 219–225.
Zhou J, Li L, Tang S, Cao X, Li Z, Li W et al (2008). Effects of serotonin depletion on the hippocampal GR/MR and BDNF expression during the stress adaptation. Behav Brain Res 195: 129–138.
Acknowledgements
We thank the individuals who participated in this study; The SardiNIA team thanks Monsignore Piseddu (Bishop of Ogliastra), the mayors of the four Sardinian towns (Lanusei, Ilbono, Arzana, and Elini), and the head of the Public Health Unit ASL4 for cooperation. We thank Professor Antonio Cao for his leadership of the SardiNIA project. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.
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Paul T. Costa, Jr receives royalties from the Revised NEO Personality Inventory. The authors declare no other conflict of interest.
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Terracciano, A., Tanaka, T., Sutin, A. et al. BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism. Neuropsychopharmacol 35, 1083–1089 (2010). https://doi.org/10.1038/npp.2009.213
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DOI: https://doi.org/10.1038/npp.2009.213
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