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Shared and specific genetic risk factors for lifetime major depression, depressive symptoms and neuroticism in three population-based twin samples

  • Kenneth S. Kendler (a1) (a2), Charles O. Gardner (a1) (a2), Michael C. Neale (a1) (a2), Steve Aggen (a1) (a2), Andrew Heath (a3), Lucía Colodro-Conde (a4), Baptiste Couvyduchesne (a4) (a5) (a6), Enda M. Byrne (a4) (a6), Nicholas G. Martin (a4) (a7) and Nathan A. Gillespie (a1) (a2) (a4)...



Vulnerability to depression can be measured in different ways. We here examine how genetic risk factors are inter-related for lifetime major depression (MD), self-report current depressive symptoms and the personality trait Neuroticism.


We obtained data from three population-based adult twin samples (Virginia n = 4672, Australia #1 n = 3598 and Australia #2 n = 1878) to which we fitted a common factor model where risk for ‘broadly defined depression’ was indexed by (i) lifetime MD assessed at personal interview, (ii) depressive symptoms, and (iii) neuroticism. We examined the proportion of genetic risk for MD deriving from the common factor v. specific to MD in each sample and then analyzed them jointly. Structural equation modeling was conducted in Mx.


The best fit models in all samples included additive genetic and unique environmental effects. The proportion of genetic effects unique to lifetime MD and not shared with the broad depression common factor in the three samples were estimated as 77, 61, and 65%, respectively. A cross-sample mega-analysis model fit well and estimated that 65% of the genetic risk for MD was unique.


A large proportion of genetic risk factors for lifetime MD was not, in the samples studied, captured by a common factor for broadly defined depression utilizing MD and self-report measures of current depressive symptoms and Neuroticism. The genetic substrate for MD may reflect neurobiological processes underlying the episodic nature of its cognitive, motor and neurovegetative manifestations, which are not well indexed by current depressive symptom and neuroticism.


Corresponding author

Author for correspondence: Kenneth S. Kendler, E-mail:


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Aggen, SH, Neale, MC and Kendler, KS (2005) DSM criteria for major depression: evaluating symptom patterns using latent-trait item response models. Psychological Medicine 35, 475487.
Akaike, H (1987) Factor analysis and AIC. Psychometrika 52, 317332.
American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders, 3rd Edn. Washington, DC: American Psychiatric Association.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th Edn. Washington, DC: American Psychiatric Association.
Amstadter, AB, Myers, JM and Kendler, KS (2014) Psychiatric resilience: longitudinal twin study. British Journal of Psychiatry 205, 275280.
Bech, P, Jorgensen, B, Jeppesen, K, Loldrup, PD and Vanggaard, T (1986) Personality in depression: concordance between clinical assessment and questionnaires. Acta Psychiatrica Scandinavica 74, 263268.
Bedford, A and Deary, IJ (1997) The personal disturbance scale (DSSI/sAD): development, use and structure. Personality and Individual Differences 22, 493510.
Berrios, GE (1982) History of the affective disorders. In Paykel, ES (ed.) Handbook of Affective Disorders, London, UK: Churchill Livingstone, pp. 4356.
Berrios, GE (1988) Depressive and manic states during the nineteenth century. In Georgotas, A and Cancro, R (eds) Depression and Mania, New York, NY: Elsevier, pp. 1325.
Boyd, JH, Weissman, MM, Thompson, WD and Myers, JK (1982) Screening for depression in a community sample. Understanding the discrepancies between depression symptom and diagnostic scales. Archives of General Psychiatry 39, 11951200.
Bromet, EJ, Andrade, LH, Bruffaerts, R, Williams, DR (2018) Major depressive disorder. In Scott, KM, deJonge P, Stein DJ, Kessler RC. (eds), Mental Disorders Around the World: Facts and Figures From the World Mental Health Surveys, 1st Edn. New York, NY: Cambridge University Press, pp. 4156.
Chodoff, P (1972) The depressive personality. A critical review. Archives of General Psychiatry 27, 666673.
Cohen, J (1960) A coefficient of agreement for nominal scales. Educational and Psychological Measurement XX, 3746.
Derogatis, LR, Lipman, RS and Covi, L (1973) SCL-90: an outpatient psychiatric rating scale–preliminary report. Psychopharmacology Bulletin 9, 1328.
Duggan, CF, Sham, P, Lee, AS and Murray, RM (1991) Does recurrent depression lead to a change in neuroticism? Psychological Medicine 21, 985990.
Eysenck, HJ (1953) The Structure of Human Personality, 1st Edn. London: Methuen & Co. LTD.
Eysenck, HJ and Eysenck, SBG (1975) Manual of the Eysenck Personality Questionnaire. London: Hodder and Stoughton.
Eysenck, SBG, Eysenck, HJ and Barrett, P (1985) A revised version of the psychoticism scale. Personality and Individual Differences 6, 2129.
Falconer, DS (1965) The inheritance of liability to certain diseases, estimated from the incidence among relatives. Annals of Human Genetics 29, 5176.
Fergusson, DM, Horwood, LJ and Lawton, JM (1989) The relationships between neuroticism and depressive symptoms. Social Psychiatry and Psychiatric Epidemiology 24, 275281.
Foley, DL, Neale, MC and Kendler, KS (2001) Genetic and environmental risk factors for depression assessed by subject-rated symptom check list versus structured clinical interview. Psychological Medicine 31, 14131423.
Foulds, GA and Bedford, A (1975) Hierarchy of classes of personal illness. Psychological Medicine 5, 181192.
Fried, EI (2016) The 52 symptoms of major depression: lack of content overlap among seven common depression scales. Journal of Affective Disorders 208, 191197.
Hirschfeld, RM, Klerman, GL, Clayton, PJ and Keller, MB (1983) Personality and depression. Empirical findings. Archives of General Psychiatry 40, 993998.
Jackson, SW (1986) Melancholia and Depression: From Hippocratic Times to Modern Times. New Haven: Yale University Press.
Jardine, R, Martin, NG and Henderson, AS (1984) Genetic covariation between neuroticism and the symptoms of anxiety and depression. Genetic Epidemiology 1, 89107.
Judd, LL (1997) Pleomorphic expressions of unipolar depressive disease: summary of the 1996 CINP president's workshop. Journal of Affective Disorders 45, 109116.
Kendler, KS (2016) The phenomenology of major depression and the representativeness and nature of DSM criteria. American Journal of Psychiatry 173, 771780.
Kendler, KS (2017) The genealogy of major depression: symptoms and signs of melancholia from 1880–1900. Molecular Psychiatry 22, 15391553.
Kendler, KS and Prescott, CA (1999) A population-based twin study of lifetime major depression in men and women. Archives of General Psychiatry 56, 3944.
Kendler, KS and Prescott, CA (2006) Genes, Environment, and Psychopathology: Understanding the Causes of Psychiatric and Substance Use Disorders, 1st Edn. New York: Guilford Press (26 July 2006).
Kendler, KS and Myers, J (2010) The genetic and environmental relationship between major depression and the five-factor model of personality. Psychological Medicine 40, 801806.
Kendler, KS and Gardner, CO (2011) A longitudinal etiologic model for symptoms of anxiety and depression in women. Psychological Medicine 41, 20352045.
Kendler, KS, Neale, MC, Kessler, RC, Heath, AC and Eaves, LJ (1993) A longitudinal twin study of personality and major depression in women. Archives of General Psychiatry 50, 853862.
Kendler, KS, Gatz, M, Gardner, C and Pedersen, NL (2006) Personality and major depression: a Swedish longitudinal, population-based twin study. Archives of General Psychiatry 63, 11131120.
Kraepelin, E (1990) Manic Depressive Insanity. In Quen, J(ed.) Psychiatry, A Textbook for Students and Physicians (Translation of the 6th Edition of Psychiatrie-Translator Volume 2-Sabine Ayed), Canton, MA: Science History Publications, pp. 272322.
Lo, MT, Hinds, DA, Tung, JY, Franz, C, Fan, CC, Wang, Y, Smeland, OB, Schork, A, Holland, D, Kauppi, K, Sanyal, N, Escott-Price, V, Smith, DJ, O'Donovan, M, Stefansson, H, Bjornsdottir, G, Thorgeirsson, TE, Stefansson, K, McEvoy, LK, Dale, AM, Andreassen, OA and Chen, CH (2017) Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders. Nature Genetics 49, 152156.
Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Wray, NR and Sullivan, PF (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics 50, 668681.
Martin, NG and Martin, PG (1975) The inheritance of scholastric abilities in a sample of twins. I. Ascertainments of the sample and diagnosis of zygosity. Annals of Human Genetics 39, 213218.
Mayer-Gross, W, Slater, E and Roth, M (1954) Clinical Psychiatry, 1st Edn. London: Cassell and Company LTD.
Neale, MC and Miller, MB (1997) The use of likelihood-based confidence intervals in genetic models. Behavior Genetics 27, 113120.
Neale, MC, Boker, SM, Xie, G and Maes, HH (2003) Mx: Statistical Modeling, 6th Edn. Richmond, VA: Dept. of Psychiatry, Virginia Commonwealth University Medical School.
Neale, MC, Hunter, MD, Pritikin, JN, Zahery, M, Brick, TR, Kirkpatrick, RM, Estabrook, R, Bates, TC, Maes, HH and Boker, SM (2016) Openmx 2.0: extended structural equation and statistical modeling. Psychometrika 81, 535549.
Ooki, S, Yamada, K, Asaka, A and Hayakawa, K (1990) Zygosity diagnosis of twins by questionnaire. Acta Geneticae Medicae et Gemellologiae (Roma.) 39, 109115.
Ormel, J, Oldehinkel, AJ and Vollebergh, W (2004) Vulnerability before, during, and after a major depressive episode: a 3-wave population-based study. Archives of General Psychiatry 61, 990996.
Orstavik, RE, Kendler, KS, Czajkowski, N, Tambs, K and Reichborn-Kjennerud, T (2007) The relationship between depressive personality disorder and major depressive disorder: a population-based twin study. American Journal of Psychiatry 164, 18661872.
R Development Core Team (2018) R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing. Online Source.
Radloff, LS (1977) The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1, 385401.
Riso, LP, Klein, DN, Ferro, T, Kasch, KL, Pepper, CM, Schwartz, JE and Aronson, TA (1996) Understanding the comorbidity between early-onset dysthymia and cluster B personality disorders: a family study. American Journal of Psychiatry 153, 900906.
Rorsman, B, Grasbeck, A, Hagnell, O, Lanke, J, Ohman, R, Ojesjo, L and Otterbeck, L (1990) A prospective study of first-incidence depression. The Lundby study, 1957–72. British Journal of Psychiatry 156, 336342.
Schneider, K (1958) Psychopathic Personalities. London: Cassell.
Shea, MT, Leon, AC, Mueller, TI, Solomon, DA, Warshaw, MG and Keller, MB (1996) Does major depression result in lasting personality change? American Journal of Psychiatry 153, 14041410.
Spitzer, RL and Williams, JBW (1985) Structured Clinical Interview for DSM-III-R (SCID). New York: Biometrics Research Department, New York State Psychiatric Institute.
Spitzer, RL, Endicott, J and Robins, E (1975) Research Diagnostic Criteria for A Selected Group of Functional Disorders, 2 Edn. New York: New York Psychiatric Institute.
Sullivan, PF, Agrawal, A, Bulik, CM, Andreassen, OA, Borglum, AD, Breen, G, Cichon, S, Edenberg, HJ, Faraone, SV, Gelernter, J, Mathews, CA, Nievergelt, CM, Smoller, JW and O'Donovan, MC (2018) Psychiatric genomics: an update and an agenda. American Journal of Psychiatry 175, 1527.
Trede, K, Salvatore, P, Baethge, C, Gerhard, A, Maggini, C and Baldessarini, RJ (2005) Manic-depressive illness: evolution in Kraepelin's textbook, 1883–1926. Harvard Review of Psychiatry 13, 155178.
Weissman, MM and Myers, JK (1978) Affective disorders in a US urban community: the use of research diagnostic criteria in an epidemiological survey. Archives of General Psychiatry 35, 13041311.
Wender, PH, Kety, SS, Rosenthal, D, Schulsinger, F, Ortmann, J and Lunde, I (1986) Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders. Archives of General Psychiatry 43, 923929.
Zeiss, AM and Lewinsohn, PM (1988) Enduring deficits after remissions of depression: a test of the scar hypothesis. Behaviour Research and Therapy 26, 151158.


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Shared and specific genetic risk factors for lifetime major depression, depressive symptoms and neuroticism in three population-based twin samples

  • Kenneth S. Kendler (a1) (a2), Charles O. Gardner (a1) (a2), Michael C. Neale (a1) (a2), Steve Aggen (a1) (a2), Andrew Heath (a3), Lucía Colodro-Conde (a4), Baptiste Couvyduchesne (a4) (a5) (a6), Enda M. Byrne (a4) (a6), Nicholas G. Martin (a4) (a7) and Nathan A. Gillespie (a1) (a2) (a4)...


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