Cited by 224Anxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesPersonality Traits and PsychologyGenetic Associations and Epidemiology

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Genetic and Environmental Sources of Covariation Between Generalized Anxiety Disorder and Neuroticism

Hettema, John M., Prescott, Carol A., Kendler, Kenneth S.·2004·American Journal of Psychiatry

DOI 10.1176/appi.ajp.161.9.1581

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Abstract

OBJECTIVE: The authors examined the sources of covariation between generalized anxiety disorder and the personality trait of neuroticism. Because women have higher levels of neuroticism and twice the risk of lifetime generalized anxiety disorder of men, gender-specific effects were also explored. METHOD: Lifetime generalized anxiety disorder and neuroticism were assessed in more than 8,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Sex-limited Cholesky structural equation models were used to decompose the correlations between generalized anxiety disorder and neuroticism into genetic and environmental components, including sex-specific factors. RESULTS: Genetic correlations between generalized anxiety disorder and neuroticism were high and differed (nonsignificantly) between men and women (1.00 and 0.58, respectively). When nonsignificant gender differences were removed from the models, correlations between generalized anxiety disorder and neuroticism were estimated at 0.80 (95% confidence interval=0.52-1.00). The individual-specific environmental correlation between generalized anxiety disorder and neuroticism was estimated at 0.20 for both genders. CONCLUSIONS: There is substantial overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability for generalized anxiety disorder, irrespective of gender. The life experiences that increase vulnerability to generalized anxiety disorder, however, have only modest overlap with those that contribute to an individual's level of neuroticism.

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Ganzer, C. A., & Jacobs, A. R. (2016) · American Journal of Men s Health · doi:10.1177/1557988316631624 · Cited by 51
The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women
Xia, J., He, Q., Li, Y., Xie, D., Zhu, S., Chen, J., Shen, Y., Zhang, N., Wei, Y., Chen, C., et al. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.06.053 · Cited by 59
“, 2002) which also contributes to the correlation between MDD and anxiety disorders (Hettema et al., 2004; Hettema et al., 2006; Jardine et al., 1984; Kendler et al., 2007).”
Background
Identifying interactions between genes and early environment in the mouse
Carola, V., Frazzetto, G., & Gross, C. T. (2005) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2005.00152.x · Cited by 49
“…et al. 1999; Chapman et al. 2004; Kendler et al. 2000), and studies taking into account interactions between environmental and genetic factors have been more successful in predicting disease susceptibility (Caspi et al. 2002; Caspi et al. 2003; Gross & Hen 2004; Hettema et al. 2004; Kendler 2001).”
Background
Sex Differences in PTSD
Christiansen, D., & Elklit, A. (2012) · Post Traumatic Stress Disorders in a Global Context · doi:10.5772/28363 · Cited by 56
“disorders, including depression and anxiety disorders (Hettema et al., 2004; Kendler et al., 2004).”
Background
Psychological adjustment one year after the diagnosis of breast cancer: A prototype study of delayed post‐traumatic stress disorder
Elklit, A., & Blum, A. (2010) · British Journal of Clinical Psychology · doi:10.1348/014466510x527676 · Cited by 48
The role of personality in comorbidity among anxiety and depressive disorders in primary care and specialty care: a cross-sectional analysis
Spinhoven, P., de Rooij, M., Heiser, W. J., Smit, J. H., & Penninx, B. W. J. H. (2009) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2009.05.002 · Cited by 45
“Because Neuroticism may be heritable [36–38] and may account for the onset, overlap and course of depression and anxiety [22], the possibility of a common genetic liability between Neuroticism and comorbid internalized disorders seems a promising avenue for further research [39,40].”
Background
Personality Dimensions as Common and Broadband-Specific Features for Internalizing and Externalizing Disorders
Hink, L. K., Rhee, S. H., Corley, R. P., Cosgrove, V. E., Hewitt, J. K., Schulz‐Heik, R. J., Lahey, B. B., & Waldman, I. D. (2013) · Research on Child and Adolescent Psychopathology · doi:10.1007/s10802-013-9730-3 · Cited by 46
“…studies have demonstrated common genetic influences between neuroticism and psychiatric disorders (Carey and DiLalla 1994; Fanous et al. 2002; Hettema et al. 2004; Hettema et al. 2006; Jardine et al. 1984; Kendler et al. 2007; Mackinnon et al. 1990; Singh and Waldman 2010) and between…”
Background
Antidepressant Effects on Emotional Temperament: Toward a Biobehavioral Research Paradigm for Major Depressive Disorder
Soskin, D. P., Carl, J. R., Alpert, J. E., & D, M. F. M. (2012) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2012.00318.x · Cited by 46
“Twin studies have found a high degree of overlap between the genetic factors thought to underlie high NA, measured as neuroticism, and anxiety and depressive disorders [25,26].”
Background
Patterns and predictors of comorbidity of DSM-IV anxiety disorders in a clinical sample of children and adolescents
Leyfer, O. T., Gallo, K. P., Cooper‐Vince, C. E., & Pincus, D. B. (2013) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2013.01.010 · Cited by 45
Neuroticism-related personality traits are associated with posttraumatic stress after abortion: findings from a Swedish multi-center cohort study
Lundell, I. W., Poromaa, I. S., Ekselius, L., Georgsson, S., Frans, Ö., Helström, L., Högberg, U., & Svanberg, A. S. (2017) · BMC Women s Health · doi:10.1186/s12905-017-0417-8 · Cited by 42
“The findings is in accordance with previous studies indicating that high scores of Neuroticism is associated with PTSD [13, 16, 23] especially in women [22, 38].”
Result
Exploring the boundary between temperament and generalized anxiety disorder: A receiver operating characteristic analysis
Rettew, D. C., Doyle, A., Kwan, M., Stanger, C., & Hudziak, J. J. (2006) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2006.02.002 · Cited by 41
“A large twin study conducted in Australia (Jardine, Martin, & Henderson, 1984) reported the genetic correlation between neuroticism and anxiety to be approximately .8. Hettema, Prescott, and Kendler (2004) recently found evidence that not only is there a high degree of correlation between neuroticism and generalized a…”
Background
Neurobiology of Generalized Anxiety Disorder
Stein, M. B. (2009) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.s.7002.03 · Cited by 41
The many faces of anxiety-neurobiological correlates of anxiety phenotypes
Andreescu, C., Mennin, D. S., Tudorascu, D., Sheu, L. K., Walker, S. E., Banihashemi, L., & Aizenstein, H. J. (2015) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2015.08.013 · Cited by 42
“Additionally, personality traits such as neuroticism are highly comorbid with anxiety disorders (Clark et al., 1994; Hettema et al., 2004, 2006).”
Background
Imaging Genomics Applied to Anxiety, Stress Response, and Resiliency
Xu, K., Ernst, M., & Goldman, D. A. (2006) · Neuroinformatics · doi:10.1385/ni:4:1:51 · Cited by 38
“Anxiety is a heritable complex trait in humans (Stevenson et al., 1992; Eley, 1999; Eley et al., 2003; Hettema et al., 2004) and other species including nonhuman primates and rodents (Williamson et al.”
Background
The big two personality traits and adolescents’ complete mental health: The mediation role of perceived school stress.
Tian, L., Jiang, S., & Huebner, E. S. (2018) · School Psychology · doi:10.1037/spq0000257 · Cited by 37
The Role of Neuroticism and Experiential Avoidance in Predicting Anxiety and Depression Symptoms: Mediating Effect of Emotion Regulation
Mohammadkhani, P., Abasi, I., Pourshahbaz, A., Mohammadi, A., & Fatehi, M. (2016) · Iranian Journal of Psychiatry and Behavioral Sciences · doi:10.17795/ijpbs-5047 · Cited by 36
“While difficulties in emotion regulation and maladaptive emotion regulation strategies contribute to emotional disorders, personality traits such as neuroticism may also play a pivotal role in etiology and maintenance of emotional disorders (29, 30).”
Background
Is the Generalized Anxiety Disorder Symptom of Worry Just Another Form of Neuroticism?
Hale, W. W., Klimstra, T. A., & Meeus, W. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.09m05506blu · Cited by 37
Self-rated importance of religion predicts one-year outcome of patients with panic disorder
Bowen, R., Baetz, M., & D’Arcy, C. (2006) · Depression and Anxiety · doi:10.1002/da.20157 · Cited by 33
“Anxiety symptoms were the target of treatment, and worry and stress are more directly associated with anxiety and phobias than with depression [Hettema et al., 2004].”
The effects of personality traits on quality of life
Bal, M. D., & Şahin, N. H. (2011) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e31821e2494 · Cited by 32
“Studies have shown that women who have neurotic personality traits are much more vulnerable to both depression(6,7,16) and anxiety.(17,18) In similar studies, it was determined that there is a strong relationship between depression and neuroticism(8,15,19) and a moderate relationship(15) between depression and introve…”
Background
TMPRSS9 and GRIN2B Are Associated with Neuroticism: a Genome-Wide Association Study in a European Sample
Aragam, N., Wang, K.-S., Anderson, J. L., & Liu, X. (2012) · Journal of Molecular Neuroscience · doi:10.1007/s12031-012-9931-1 · Cited by 33
“Neuroticism also has genetic covariance with depression and anxiety (Jardine et al. 1984; Kendler et al. 1992, 1993; Fanous et al. 2002; Hettema et al. 2004; Hueazo-Diaz et al. 2005; Hettema et al. 2006b).”
Background
Family Matters: Happiness in Nuclear Families and Twins
Nes, R. B., Czajkowski, N., & Tambs, K. (2010) · Behavior Genetics · doi:10.1007/s10519-010-9365-x · Cited by 41
“2002) and generalised anxiety disorder (Hettema et al. 2004) as well as for neuroticism and subthreshold symptoms of anxiety and depression (Jardine et al.”
Background
Anxiety symptoms in obsessive-compulsive disorder and generalized anxiety disorder
Citkowska-Kisielewska, A., Rutkowski, K., Sobański, J. A., Dembińska, E., & Mielimąka, M. (2019) · Psychiatria Polska · doi:10.12740/pp/105378 · Cited by 34
“…different anxiety disorders is believed to be a clinical sign of common etiopathogenetic factors, including a common genetic and neurobiological background, expressed in such features as the domination of negative affect, ‛neuroticism’, avoidance of threats, or ‛intolerance of uncertainty’ [8–11].”
Generalized anxiety disorder
Hidalgo, R. B., & Sheehan, D. V. (2012) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52002-9.00019-x · Cited by 30
Use of an estradiol-based combined oral contraceptives has no influence on attentional bias or depressive symptoms in healthy women
Scheuringer, A., Lundin, C., Derntl, B., Pletzer, B. A., & Poromaa, I. S. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104544 · Cited by 30
Common mental health disorders.
Bessant, M., & Ekers, D. (2011) · PubMed · Cited by 28
New Approaches to the Genetic Analysis of Neuroticism and Anxiety
Fullerton, J. M. (2005) · Behavior Genetics · doi:10.1007/s10519-005-9000-4 · Cited by 27
“Neuroticism manifests at one extreme as anxiety, depression, moodiness, low self-esteem, and diffidence (Cloninger, 1994; Digman, 1990; Dreary and Matthews, 1993; Loehlin and Nichols, 1976; Zuckerman et al., 1988), and genetic susceptibility to neuroticism is shared with two other common psychiatric disorders, major d…”
Background
Predictors of Clinical Improvement in a Randomized Effectiveness Trial for Primary Care Patients With Panic Disorder
Chavira, D. A., Stein, M. B., Golinelli, D., Sherbourne, C. D., Craske, M. G., Sullivan, G., Bystritsky, A., & Roy‐Byrne, P. (2009) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0b013e3181b97d4d · Cited by 26
“In both clinical and general population studies alike, neuroticism has been identified as a risk factor for Axis I and Axis II disorders (Hettema et al., 2004; Jylha and Isometsa, 2006; Miller and Pilkonis, 2006).”
Background
QT interval duration in apparently healthy men is associated with depression-related personality trait neuroticism
Minoretti, P., Politi, P., Martinelli, V., Emanuele, E., Bertona, M., Falcone, C., & Geroldi, D. (2006) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2006.01.001 · Cited by 26
“Neuroticism is also known to possess good psychometric properties of item and construct validity, stability, and cross-cultural validation [21].”
Background
Is it Generalized Anxiety Disorder or Poverty? An Examination of Poor Mothers and Their Children
Baer, J. C., Kim, M., & Wilkenfeld, B. F. (2012) · Child and Adolescent Social Work Journal · doi:10.1007/s10560-012-0263-3 · Cited by 26
A longitudinal examination of psychosocial impairment across the anxiety disorders
Naragon‐Gainey, K., Gallagher, M. W., & Brown, T. A. (2013) · Psychological Medicine · doi:10.1017/s0033291713001967 · Cited by 28
“…that GAD may be the ‘basic emotional disorder’ (e.g. Brown et al. 1998) because it is largely isomorphic with neuroticism, a trait that is closely associated with co-morbidity among the mood and anxiety disorders (e.g. Hettema et al. 2004; Watson et al. 2005; Weinstock & Whisman, 2006).”
Background
Neuroimaging and Human Genetics
Winterer, G., Hariri, A. R., Goldman, D. A., & Weinberger, D. R. (2005) · International review of neurobiology · doi:10.1016/s0074-7742(05)67010-9 · Cited by 26
Identification of quantitative trait loci for locomotor activation and anxiety using closely related inbred strains
Bailey, J. S., Grabowski-Boase, L., Steffy, B. M., Wiltshire, T., Churchill, G. A., & Tarantino, L. M. (2008) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2008.00415.x · Cited by 25
“A clear genetic basis for neuroticism, the personality dimension most highly correlated with anxiety-related disorders, exists as well, and the genetic factors associated with both exhibit substantial overlap (Hettema et al. 2004; Jardine et al. 1984; Kendler et al. 1993).”
Background
Stress-Induced and Fear Circuitry Disorders: Refining the Research Agenda for DSM-V
Charney, D. S., Sirovatka, P. J., & Regier, D. A. (2008) · American Psychiatric Association Publishing eBooks · doi:10.1176/appi.books.9780890427750 · Cited by 25
Adult Romantic Attachment, Negative Emotionality, and Depressive Symptoms in Middle Aged Men: A Multivariate Genetic Analysis
Franz, C. E., York, T. P., Eaves, L. J., Prom‐Wormley, E. C., Jacobson, K. C., Lyons, M. J., Grant, M. D., Xian, H., Panizzon, M. S., Jimenez, E., et al. (2011) · Behavior Genetics · doi:10.1007/s10519-010-9428-z · Cited by 24
“The heritability estimates of the personality trait of neuroticism/ negative emotionality (variously defined) range from 30 to 60% and may be higher in men than in women (Eaves et al. 1998; Hettema et al. 2004; Jang et al. 1996; Kendler et al. 2006a, b).”
Background
The Effects of Neuroticism, Extraversion, and Positive and Negative Life Events on a One-Year Course of Depressive Symptoms in Euthymic Previously Depressed Patients Versus Healthy Controls
Spinhoven, P., Elzinga, B. M., Roelofs, K., Hovens, J. G. F. M., van Oppen, P., Zitman, F. G., & Penninx, B. W. J. H. (2011) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0b013e318229d21f · Cited by 25
“, 1994) may both be heritable (e.g., Fanous et al., 2002; Hettema et al., 2004; Viken et al., 1994) and account not only for the onset and course of depression but also for its recurrence.”
Background
A translational approach to the genetics of anxiety disorders
McGregor, N. W., Dimatelis, J. J., van Zyl, P. J., Hemmings, S. M. J., Kinnear, C. J., Russell, V. A., Stein, D. J., & Löchner, C. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.12.030 · Cited by 26

Authors: Hettema, J. M., Prescott, C. A., & Kendler, K. S.
Affiliations: Virginia Commonwealth University (US)
ORCID: Hettema, John M.
Prescott, Carol A.
Kendler, Kenneth S.
Venue: American Journal of Psychiatry
Publisher: American Psychiatric Association Publishing
Published: 2004-09-01
Volume: 161
Issue: 9
Pages: 1581-1587
ISSN: 0002-953X (ISSN-L)
1535-7228
DOI: 10.1176/appi.ajp.161.9.1581
OpenAlex: W2079459508
Cited by: 224
References: 24
Citations by year: 2026: 2 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 13 · 2020: 6 · 2019: 12 · 2018: 6 · 2017: 9 · 2016: 4 · 2015: 8 · 2014: 4 · 2013: 8 · 2012: 11
FWCI: 16.24
Type: journal article
Language: en
Open access: closed
Locations: American Journal of Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Alcohol Abuse and Alcoholism (R01AA009095, AA-09095)
National Institute of Mental Health (K08MH066277, R01MH040828, MH 40828, MH/AA/DA-49492)
National Institute on Drug Abuse (DA11287, R01DA011287)
Topics: Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Social Sciences › Psychology › Clinical Psychology › Personality Traits and Psychology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: generalized anxiety disorder, neuroticism, personality traits, genetic correlation, environmental correlation, sex differences, twin studies, heritability
MeSH terms: Adult, Anxiety Disorders, Diseases in Twins, Female, Humans, Male, Middle Aged, Models, Genetic, Neurotic Disorders, Personality, Personality Inventory, Phenotype, Psychiatric Status Rating Scales, Risk Factors, Sex Factors, Social Environment, Twins, Dizygotic, Twins, Monozygotic, Genetic Variation, Genetic Predisposition to Disease

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Genetic and Environmental Sources of Covariation Between Generalized Anxiety Disorder and Neuroticism

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