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Genetic Underpinnings of Neuroticism: A Replication Study
ISSN: 2155-6105

Journal of Addiction Research & Therapy
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Genetic Underpinnings of Neuroticism: A Replication Study

Lily R Aleksandrova1,2, Renan P. Souza1,3, Michael R. Bagby4, David M. Casey5, David C. Hodgins5, Garry J. Smith6, Rob J. Williams7, Don P. Schopflocher8, Rob T. Wood9, Nady El-Guebaly10, James L. Kennedy1,3# and Daniela S. S. Lobo1,3,11*#
1Neuroscience Department, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON, Canada
2Department of Pharmacology, University of Toronto, Toronto, ON, Canada
3Department of Psychiatry, University of Toronto, Toronto, ON, Canada
4Clinical Research Department, Centre for Addiction and Mental Health, Toronto, ON, Canada
5Department of Psychology, University of Calgary, Calgary, AB, Canada
6Faculty of Extension, University of Alberta, Edmonton, AB, Canada
7School of Health Sciences, University of Lethbridge, Lethbridge, AB, Canada
8Faculty of Nursing, University of Alberta, Edmonton, AB, Canada
9Department of Sociology, University of Lethbridge, Lethbridge, AB, Canada
10Department of Psychiatry, Division of Addiction, University of Calgary, Calgary, AB, Canada
11Problem Gambling Service, Addictions Program, Centre for Addiction and Mental Health, Toronto, ON, Canada
#Contributed equally to this work
*Corresponding Author: Daniela S. S. Lobo, M.D, Ph.D, Centre for Addiction and Mental Health, 33 Russell St, RS 3039 Toronto, ON - M5S 2S1, Canada, Tel: 1-416-535-8501 Exn. 6568, Fax: 1-416-979-4666, Email: [email protected]

Received: 12-Nov-2012 / Accepted Date: 12-Jan-2012 / Published Date: 16-Jan-2012 DOI: 10.4172/2155-6105.1000119 /


Background: Neuroticism, as defined and measured by the NEO Personality Inventory (Neuroticism Extraversion and Openness Personality Inventory), is a core personality trait reflecting an individual’s emotional reactivity. High neuroticism is thought to be an important vulnerability factor for various psychiatric disorders in the general population, including substance abuse, depression, anxiety, and psychosis. Recent findings support the hypothesis that genetic factors underlying the neuroticism trait could increase the susceptibility to psychiatric disorders. The current study aimed to replicate genetic associations with high neuroticism previously reported in the literature.
Methods: We genotyped four polymorphisms: CNR1 (rs7766029), GABRA2 (rs9291283), GABRA6 (rs3219151) and MAMDC1 (rs7151262) in 215 healthy Caucasian subjects, who completed a short version of the NEO-PI. NEO neuroticism scores of the three genotype groups were compared using ANCOVA, with age as a covariate.
Results: All four genetic polymorphisms were found to be significantly associated with NEO neuroticism scores (p < 0.0025), but not with any other NEO personality domain. Conclusion: Our results corroborate other studies proposing a role for the GABAergic and cannabinoid systems in the modulation of affective states and stress responses, as measured through neuroticism scores. It is important to replicate the genetic findings of neuroticism, in order to gain a better understanding of this personality domain that has been reported as an important risk factor for mood and anxiety disorders and substance addiction.

Keywords: NEO; Neuroticism; Genetics


Neuroticism is a core personality trait that reflects an individual’s emotional reactivity, with an estimated heritability of 40 to 60% [1-3]. Individuals who score high on measures of neuroticism tend to be more sensitive to negative mood states and to have excessive responses to environmental stresses. Maladaptive efforts to regulate affect and cope with negative emotional life events can result in the development of an addiction or a psychiatric disorder [4-7]. In fact, high levels of neuroticism have been extensively linked to psychiatric disorders, such as depression [8-10], anxiety [7,11] and substance use disorders [12,13]. Neuroticism, as assessed by the NEO Personality Inventory (Neuroticism Extraversion and Openness Personality Inventory), is therefore considered an important vulnerability factor for psychopathology [14,15], and a strong positive correlation exists between NEO neuroticism scores and the risk of relapse in several psychiatric conditions, including psychosis, depression and substance abuse [12,16,17]. Furthermore, neuroticism scores and negative life events were found to be the two strongest predictors of onset of psychotic and depressive symptoms during remission and relapse from both alcoholism and opioid addiction [12,17,18]. Taken together, these results suggest that neuroticism may be an underlying vulnerability factor for mental illness and addiction.

Recent findings support the hypothesis that genetic factors underlying individual differences in neuroticism could increase the susceptibility to both addiction and mental illness [19,20]. Twin studies have suggested a heritability coefficient in the range of 0.4-0.6 for this personality trait, which has spurred attempts to map the genetic basis of neuroticism. The current study aimed to verify if previously reported associations of genetic variants with NEO neuroticism [3,21-26] scores would be replicated in a sample of healthy subjects of European Caucasian descent.

Subjects And Methods

Our sample of 215 unrelated healthy European Caucasian subjects (35% male, age 48.9±16.1) was collected as part of the “Leisure, Lifestyle, and Lifecycle” Project in the province of Alberta, Canada [27]. Presence of a lifetime psychiatric disorders was an exclusion criteria and was assessed through the Composite International Diagnostic Interview (CIDI) [28]. Personality traits were assessed using the NEO-FFI, which is a 60-item short version of the NEO-PI-R (Revised NEO Personality Inventory). This personality assessment measures the following five personality dimensions: Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness [14].

DNA extraction was performed on blood samples using a standard high-salt method. We genotyped four polymorphisms previously associated with neuroticism in the literature: rs7766029 in the CNR1 [24], rs9291283 in GABRA2 [26,29], rs3219151 in GABRA6 [21,25] and rs7151262 in MAMDC1 [3,23,30]. Genotyping was performed using TaqMan allele-specific assays (ABI Prism 7000/7500, Applied Biosystems, Foster City, CA). According to published guidelines, we have included four negative controls in each 96-well genotyping plate and 10% of the total sample was re-genotyped to ensure sufficient accuracy.

NEO domain scores of the three genotype groups were compared using ANCOVA with age as a covariate, implemented on the Statistical Package for the Social Sciences (SPSS), version 15.0. Age was incorporated in our model because it is a key factor influencing personality; including neuroticism scores [3,31]. The significance level was set to p=0.0025 after a Bonferroni correction for multiple testing (0.05/ 20 tests).


We obtained 100% genotyping accuracy and all polymorphisms were in Hardy-Weinberg equilibrium (p > 0.05). Our sample had over 80% statistical power to detect association of the GABRA2 polymorphism (lowest allele frequency among the evaluated polymorphisms) with a minimum r² of 2.5% [32]. All four variants were found to be significantly associated with neuroticism scores in our sample (p < 0.0025). We have not observed significant association of these polymorphisms with any of the other four NEO personality dimensions analyzed. The common allelic variants of CNR1 rs7766029 and GABRA2 rs9291283 were associated with higher neuroticism scores than the rare alleles; while the common alleles of GABRA6 rs3219151 and MAMDC1 rs7151262 were associated with lower neuroticism scores (Table 1).


We replicated previously reported associations of polymorphisms in GABRA2 and 6, CNR1, and MAMDC1 with the personality trait of neuroticism. Taken together with previous results, the current study supports the roles of the endocannabinoid and GABAergic neurotransmitter systems in the regulation of emotionality and responsiveness to stress. Limitations to this study would include a moderate sample size, but our power calculations showed we would have 80% power to detect medium genetic effects [33]. Also, the functional role of the polymorphisms investigated here is yet to be determined.

The first genome-wide association study (GWAS) for neuroticism highlighted the significance of a common polymorphism in the mam domain-containing glycosylphosphatidyl-inositol anchor 2 gene (MAMDC1) [3], which was recently confirmed in a second GWAS [23]. Although no functional studies of rs7151262 have been published, the MAMDC1 gene is predominantly expressed in areas associated with memory and emotional regulation (hippocampus and amygdala), and is thought to be involved in regulating neuronal migration and axonal guidance [34].

Cannabinoids are known to have both anxiolytic and anxiogenic properties, implicating the endocannabinoid system in mood and stress response regulation. It has been hypothesized that temporal changes in the endocannabinoid system during development can affect a person`s emotional stability and stress responsiveness later in life [35-37]. For example, cannabis use during adolescence has been recently highlighted as a significant risk factor for the development of psychotic symptoms in adulthood [37]. Moreover, adolescent exposure to cannabinoids is associated with an earlier onset of schizophrenia [35]. Not surprisingly, genetic variants in the cannabinoid receptor 1 gene (CNR1) have been reported to be significantly associated with high neuroticism scores [24].

Genetic Variant Personality Domain Genotype ANCOVA (covariate: age)
1 1 1 2 2 2
mean n SD mean n SD mean n SD F p*
CNR1 rs7766029
1 = T
2 = C
Neuroticism 14.5 51 7.4 15.9 86 7.8 14.8 74 7.0 6.6 <0.001
Extraversion 28.5 51 6.7 29.3 86 6.4 28.5 74 6.2 1.4 0.25
Openness 29.8 51 5.8 29.5 86 6.2 30.3 74 6.2 2.1 0.09
Agreeableness 35.5 51 6.0 34.4 86 5.6 34.5 74 4.2 3.0 0.03
Conscientiousness 34.8 51 6.0 34.7 86 6.0 34.8 74 5.6 1.8 0.14
GABRA2 rs9291283
1 = C
2 = T
Neuroticism 15.3 122 8.1 14.9 80 6.6 13.6 11 5.3 6.1 <0.001
Extraversion 28.5 122 6.4 29.2 80 6.6 29.2 11 4.1 1.1 0.34
Openness 29.9 122 6.3 29.7 80 5.7 32.7 11 6.9 3.0 0.03
Agreeableness 34.8 122 5.2 34.6 80 5.6 35.6 11 4.4 2.6 0.06
Conscientiousness 35.1 122 5.7 34.6 80 6.0 33.8 11 7.0 2.2 0.09
GABRA6 rs3219151
1 = T
2 = C
Neuroticism 13.7 75 6.1 15.2 95 7.5 17.2 43 9.0 7.9 <0.0001
Extraversion 28.8 75 6.3 29.1 95 6.2 28.2 43 7.0 1.2 0.31
Openness 28.6 75 6.0 31.0 95 5.7 30.1 43 6.7 4.3 0.01
Agreeableness 34.9 75 5.0 34.2 95 5.0 35.7 43 6.1 3.6 0.02
Conscientiousness 35.5 75 5.2 34.1 95 5.6 35.3 43 7.5 3.0 0.03
MAMDC1 rs7151262
1 = G
2 = C
Neuroticism 15.1 87 7.9 14.6 85 7.2 16.1 41 7.0 6.0 <0.001
Extraversion 28.9 87 6.4 28.3 85 6.0 29.5 41 7.1 1.2 0.30
Openness 30.1 87 5.7 29.5 85 6.0 30.6 41 7.1 2.1 0.10
Agreeableness 35.4 87 5.4 34.5 85 5.3 34.0 41 5.0 3.3 0.02
Conscientiousness 35.4 87 6.3 35.0 85 5.5 33.4 41 5.7 3.0 0.03

*The significance level was set to p=0.0025 after a Bonferroni correction for multiple testing (0.05/ 20 tests).

Table 1: Association analysis between CNR1, GABRA2, GABRA6 and MAMDC1 polymorphisms with the five personality domains assessed by the NEO-FFI scale, using age as covariate (ANCOVA).

Similarly, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has long been implicated in modulating anxiety, and may therefore partially underlie the personality dimension of neuroticism [38,39]. Post-mortem studies have found that the prefrontal cortex of patients who suffered from depression or an anxiety disorder contained less GABAergic neurons [38]. Furthermore, prior genetic studies have shown associations of neuroticism with polymorphisms located in the GABAergic system genes. Common polymorphisms within the glutamic acid decarboxylase 1 (GAD1) gene, which encodes the enzyme responsible for GABA synthesis, have been significantly associated with high neuroticism scores [11]. Moreover, variants in the GABA receptor subunit alpha (GABRA) have been previously found to be associated with neuroticism and other emotional reactivityassociated traits (e.g. attenuated stress response and harm avoidance), and could confer a genetic susceptibility to major depression and anxiety disorders [25,26,29,40].

The current study investigated the association of four previously reported polymorphisms with neuroticism and these associations were replicated. Neuroticism is thought to have a moderate genetic component and may be important in the acquisition, development, and maintenance of psychiatric disorders, including substance addiction. Thus, together with previous research, our results may help clarify the genetic underpinnings of neuroticism and its role as a vulnerability factor for both mood and anxiety disorders and substance addiction.


  1. Calboli FC, Tozzi F, Galwey NW, Antoniades A, Mooser V, et al. (2010) A genome-wide association study of neuroticism in a population-based sample. PLoS One 5: e11504.
  2. Hettema JM, Prescott CA, Kendler KS (2004) Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. Am J Psychiatry 161: 1581-1587.
  3. van den Oord EJ, Kuo PH, Hartmann AM, Webb BT, Möller HJ, et al. (2008) Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Arch Gen Psychiatry 65: 1062-1071.
  4. Boyce P, Parker G (1985) Neuroticism as a predictor of outcome in depression. J Nerv Ment Dis 173: 685-688.
  5. Cuijpers P, van Straten A, Donker M (2005) Personality traits of patients with mood and anxiety disorders. Psychiatry Res 133: 229-237.
  6. Duggan C, Milton J, Egan V, McCarthy L, Palmer B, et al. (2003) Theories of general personality and mental disorder. Br J Psychiatry Suppl 44: S19-23.
  7. Jylha P, Melartin T, Isometsa E (2009) Relationships of neuroticism and extraversion with axis I and II comorbidity among patients with DSM-IV major depressive disorder. J Affect Disord 114: 110-121.
  8. Bock C, Bukh JD, Vinberg M, Gether U, Kessing LV (2010) The influence of comorbid personality disorder and neuroticism on treatment outcome in first episode depression. Psychopathology 43: 197-204.
  9. Cox BJ, McWilliams LA, Enns MW, Clara IP (2004) Broad and specific personality dimensions associated with major depression in a nationally representative sample. Compr Psychiatry 45: 246-253.
  10. Roberts SB, Kendler KS (1999) Neuroticism and self-esteem as indices of the vulnerability to major depression in women. Psychol Med 29: 1101-1109.
  11. Hettema JM, Neale MC, Myers JM, Prescott CA, Kendler KS (2006) A population-based twin study of the relationship between neuroticism and internalizing disorders. Am J Psychiatry 163: 857-864.
  12. Fisher LA, Elias JW, Ritz K (1998) Predicting relapse to substance abuse as a function of personality dimensions. Alcohol Clin Exp Res 22: 1041-1047.
  13. Grabe HJ, Mahler J, Witt SH, Schulz A, Appel K, et al. (2011) A risk marker for alcohol dependence on chromosome 2q35 is related to neuroticism in the general population. Mol Psychiatry 16: 126-128.
  14. Costa PT, McCrae RR (1992) Revised NEO personality inventory (NEO-PI-R) and NEO five-factor inventory (NEO-FFI) professional manual. Psychological Assessment Resources.
  15. Malouff JM, Thorsteinsson EB, Shutte NS (2005) The relationship between the five-factor model of personality and symptoms of clinical disorders: a meta-analysis. J Psychopathol Behav Assess 27: 101-114.
  16. Kendler KS, Kuhn J, Prescott CA (2004) The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. Am J Psychiatry 161: 631-636.
  17. Krabbendam L, Janssen I, Bak M, Bijl RV, de Graaf R, et al. (2002) Neuroticism and low self-esteem as risk factors for psychosis. Soc Psychiatry Psychiatr Epidemiol 37: 1-6.
  18. Gleeson JF, Rawlings D, Jackson HJ, McGorry PD (2005) Agreeableness and neuroticism as predictors of relapse after first-episode psychosis: a prospective follow-up study. J Nerv Ment Dis 193: 160-169.
  19. Jardine R, Martin NG, Henderson AS (1984) Genetic covariation between neuroticism and the symptoms of anxiety and depression. Genet Epidemiol 1: 89-107.
  20. Middeldorp CM, Cath DC, Van Dyck R, Boomsma DI (2005) The co-morbidity of anxiety and depression in the perspective of genetic epidemiology. A review of twin and family studies. Psychol Med 35: 611-624.
  21. Alfimova MV, Monakhov MV, Golimbet VE, Korovaitseva GI, Lyashenko GL (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.
  22. Arias B, Aguilera M, Moya J, Sáiz PA, Villa H, et al. (2011) The role of genetic variability in the SLC6A4, BDNF and GABRA6 genes in anxiety-related traits. Acta Psychiatr Scand.
  23. Heck A, Pfister H, Czamara D, Muller-Myhsok B, Putz B, et al. (2011) Evidence for associations between MDGA2 polymorphisms and harm avoidance: replication and extension of a genome-wide association finding. Psychiatr Genet 21: 257-260.
  24. Juhasz G, Chase D, Pegg E, Downey D, Toth ZG, et al. (2009) CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms. Neuropsychopharmacology 34: 2019-2027.
  25. Uhart M, McCaul ME, Oswald LM, Choi L, Wand GS (2004) GABRA6 gene polymorphism and an attenuated stress response. Mol Psychiatry 9: 998-1006.
  26. Soyka M, Preuss UW, Hesselbrock V, Zill P, Koller G, et al. (2008) GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence. J Psychiatr Res 42: 184-191.
  27. El-Guebaly N, Casey DM, Hodgins DC, Smith GJ, Williams RJ, et al. (2008) Designing a longitudinal cohort study of gambling in Alberta: rationale, methods, and challenges. J Gambl Stud 24: 479-504.
  28. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, et al. (1988) The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 45: 1069-1077.
  29. Roh S, Matsushita S, Hara S, Maesato H, Matsui T, et al. (2011) Role of GABRA2 in Moderating Subjective Responses to Alcohol. Alcohol Clin Exp Res 35: 400-407.
  30. Hettema JM, van den Oord EJ, An SS, Kendler KS, Chen X (2009) Follow-up association study of novel neuroticism gene MAMDC1. Psychiatr Genet 19: 213-214.
  31. Gonda X, Fountoulakis KN, Juhasz G, Rihmer Z, Lazary J, et al. (2009) Association of the s allele of the 5-HTTLPR with neuroticism-related traits and temperaments in a psychiatrically healthy population. Eur Arch Psychiatry Clin Neurosci 259: 106-113.
  32. Gauderman WJ (2003) Candidate gene association analysis for a quantitative trait, using parent-offspring trios. Genet Epidemiol 25: 327-338.
  33. Gauderman W, Morrison J (2006) QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies.
  34. Litwack ED, Babey R, Buser R, Gesemann M, O'Leary DD (2004) Identification and characterization of two novel brain-derived immunoglobulin superfamily members with a unique structural organization. Mol Cell Neurosci 25: 263-274.
  35. Dragt S, Nieman DH, Schultze-Lutter F, van der Meer F, Becker H, et al. (2012) Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Acta Psychiatr Scand 125: 45-53.
  36. Marco EM, Laviola G (2011) The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives. J Psychopharmacol [Epub ahead of print].
  37. Rubino T, Zamberletti E, Parolaro D (2011) Adolescent exposure to cannabis as a risk factor for psychiatric disorders. J Psychopharmacol [Epub ahead of print].
  38. Goto N, Yoshimura R, Moriya J, Kakeda S, Hayashi K, et al. (2010) Critical examination of a correlation between brain gamma-aminobutyric acid (GABA) concentrations and a personality trait of extroversion in healthy volunteers as measured by a 3 Tesla proton magnetic resonance spectroscopy study. Psychiatry Res 182: 53-57.
  39. Petty F (1995) GABA and mood disorders: a brief review and hypothesis. J Affect Disord 34: 275-281.
  40. Sen S, Villafuerte S, Nesse R, Stoltenberg SF, Hopcian J, et al. (2004) Serotonin transporter and GABAA alpha 6 receptor variants are associated with neuroticism. Biol Psychiatry 55: 244-249.

Citation: Aleksandrova LR, Souza RP, Bagby MR, Casey DM, Hodgins DC, et al. (2012) Genetic Underpinnings of Neuroticism: A Replication Study. J Addict Res Ther 3: 119. DOI: 10.4172/2155-6105.1000119

Copyright: © 2012 Aleksandrova LR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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