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Shared Genetic Factors Underlie Migraine and Depression

  • Yuanhao Yang (a1), Huiying Zhao (a1), Andrew C. Heath (a2), Pamela A. F. Madden (a2), Nicholas G. Martin (a3) and Dale R. Nyholt (a1)...

Migraine frequently co-occurs with depression. Using a large sample of Australian twin pairs, we aimed to characterize the extent to which shared genetic factors underlie these two disorders. Migraine was classified using three diagnostic measures, including self-reported migraine, the ID migraine™ screening tool, or migraine without aura (MO) and migraine with aura (MA) based on International Headache Society (IHS) diagnostic criteria. Major depressive disorder (MDD) and minor depressive disorder (MiDD) were classified using the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. Univariate and bivariate twin models, with and without sex-limitation, were constructed to estimate the univariate and bivariate variance components and genetic correlation for migraine and depression. The univariate heritability of broad migraine (self-reported, ID migraine, or IHS MO/MA) and broad depression (MiDD or MDD) was estimated at 56% (95% confidence interval [CI]: 53–60%) and 42% (95% CI: 37–46%), respectively. A significant additive genetic correlation (r G = 0.36, 95% CI: 0.29–0.43) and bivariate heritability (h 2 = 5.5%, 95% CI: 3.6–7.8%) was observed between broad migraine and depression using the bivariate Cholesky model. Notably, both the bivariate h 2 (13.3%, 95% CI: 7.0–24.5%) and r G (0.51, 95% CI: 0.37–0.69) estimates significantly increased when analyzing the more narrow clinically accepted diagnoses of IHS MO/MA and MDD. Our results indicate that for both broad and narrow definitions, the observed comorbidity between migraine and depression can be explained almost entirely by shared underlying genetically determined disease mechanisms.

Corresponding author
Address for correspondence: Yuanhao Yang and Dale R. Nyholt, Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, GPO Box 2434, Brisbane QLD 4001, Australia. E-mail: and
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Almasy, L., & Blangero, J. (2010). Variance component methods for analysis of complex phenotypes. Cold Spring Harbor Protocols, 2010, pdb top77.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed., rev.). Washington, DC: Author.
Arroyo-Quiroz, C., Kurth, T., Cantu-Brito, C., Lopez-Ridaura, R., Romieu, I., & Lajous, M. (2014). Lifetime prevalence and underdiagnosis of migraine in a population sample of Mexican women. Cephalalgia, 34, 10881092.
Bierut, L. J., Heath, A. C., Bucholz, K. K., Dinwiddie, S. H., Madden, P. A., Statham, D. J., . . . Martin, N. G. (1999). Major depressive disorder in a community-based twin sample: Are there different genetic and environmental contributions for men and women? Archives of General Psychiatry, 56, 557563.
Boker, S., Neale, M., Maes, H., Wilde, M., Spiegel, M., Brick, T., . . . Fox, J. (2011). OpenMx: An open source extended structural equation modeling framework. Psychometrika, 76, 306317.
Boomsma, D., Busjahn, A., & Peltonen, L. (2002). Classical twin studies and beyond. Nature Reviews Genetics, 3, 872882.
Breslau, N., Davis, G. C., Schultz, L. R., & Peterson, E. L. (1994). Joint 1994 wolff award presentation. Migraine and major depression: A longitudinal study. Headache, 34, 387393.
Breslau, N., Lipton, R. B., Stewart, W. F., Schultz, L. R., & Welch, K. M. (2003). Comorbidity of migraine and depression: Investigating potential etiology and prognosis. Neurology, 60, 13081312.
Breslau, N., Schultz, L. R., Stewart, W. F., Lipton, R. B., Lucia, V. C., & Welch, K. M. (2000). Headache and major depression: Is the association specific to migraine? Neurology, 54, 308313.
Buse, D. C., Manack, A. N., Fanning, K. M., Serrano, D., Reed, M. L., Turkel, C. C., & Lipton, R. B. (2012). Chronic migraine prevalence, disability, and sociodemographic factors: Results from the American migraine prevalence and prevention study. Headache, 52, 14561470.
De Moor, M. H., Boomsma, D. I., Stubbe, J. H., Willemsen, G., & de Geus, E. J. (2008). Testing causality in the association between regular exercise and symptoms of anxiety and depression. Archives of General Psychiatry, 65, 897905.
Duncan, A. E., Munn-Chernoff, M. A., Hudson, D. L., Eschenbacher, M. A., Agrawal, A., Grant, J. D., . . . Heath, A. C. (2014). Genetic and environmental risk for major depression in African-American and European-American women. Twin Research and Human Genetics, 17, 244253.
Headache Classification Committee of the International Headache, S. (2013). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia, 33, 629808.
Heath, A. C., Howells, W., Kirk, K. M., Madden, P. A., Bucholz, K. K., Nelson, E. C., . . . Martin, N. G. (2001). Predictors of non-response to a questionnaire survey of a volunteer twin panel: findings from the Australian 1989 twin cohort. Twin Research, 4, 7380.
Honkasalo, M. L., Kaprio, J., Winter, T., Heikkila, K., Sillanpaa, M., & Koskenvuo, M. (1995). Migraine and concomitant symptoms among 8167 adult twin pairs. Headache, 35, 7078.
Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves, L. J. (1992). A population-based twin study of major depression in women. The impact of varying definitions of illness. Archives of General Psychiatry, 49, 257266.
Larsson, B., Bille, B., & Pedersen, N. L. (1995). Genetic influence in headaches: A Swedish twin study. Headache, 35, 513519.
Launer, L. J., Terwindt, G. M., & Ferrari, M. D. (1999). The prevalence and characteristics of migraine in a population-based cohort: The GEM study. Neurology, 53, 537542.
Ligthart, L., Hottenga, J. J., Lewis, C. M., Farmer, A. E., Craig, I. W., Breen, G., . . . Nyholt, D. R. (2014). Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders. Human Genetics, 133, 173186.
Ligthart, L., Nyholt, D. R., Penninx, B. W., & Boomsma, D. I. (2010). The shared genetics of migraine and anxious depression. Headache, 50, 15491560.
Lipton, R. B., Dodick, D., Sadovsky, R., Kolodner, K., Endicott, J., Hettiarachchi, J., . . . ID Migraine Validation Study. (2003). A self-administered screener for migraine in primary care: The ID Migraine Validation Study. Neurology, 61, 375382.
Modgill, G., Jette, N., Wang, J. L., Becker, W. J., & Patten, S. B. (2012). A population-based longitudinal community study of major depression and migraine. Headache, 52, 422432.
Mongini, F., Keller, R., Deregibus, A., Raviola, F., Mongini, T., & Sancarlo, M. (2003). Personality traits, depression and migraine in women: A longitudinal study. Cephalalgia, 23, 186192.
Mulder, E. J., Van Baal, C., Gaist, D., Kallela, M., Kaprio, J., Svensson, D. A., . . . Palotie, A. (2003). Genetic and environmental influences on migraine: A twin study across six countries. Twin Research, 6, 422431.
Neale, M. C., Roysamb, E., & Jacobson, K. (2006). Multivariate genetic analysis of sex limitation and G x E interaction. Twin Research and Human Genetics, 9, 481489.
Nes, R. B., Czajkowski, N. O., Roysamb, E., Orstavik, R. E., Tambs, K., & Reichborn-Kjennerud, T. (2013). Major depression and life satisfaction: A population-based twin study. Journal of Affective Disorders, 144, 5158.
Nyholt, D. R., Gillespie, N. G., Heath, A. C., Merikangas, K. R., Duffy, D. L., & Martin, N. G. (2004). Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities. Genetic Epidemiology, 26, 231244.
Rijsdijk, F. V., & Sham, P. C. (2002). Analytic approaches to twin data using structural equation models. Briefings in Bioinformatics, 3, 119133.
RStudio Team. (2014). RStudio: Integrated development for R. Boston, MA: RStudio.
Saraceno, B. (2002). The WHO world health report 2001 on mental health. Epidemiologia e Psichiatria Sociale, 11, 8387.
Schur, E. A., Noonan, C., Buchwald, D., Goldberg, J., & Afari, N. (2009). A twin study of depression and migraine: Evidence for a shared genetic vulnerability. Headache, 49, 14931502.
Science Meanderthal. (2012). Cholesky decomposition of variance-covariance matrices in the classic twin study. Science Meanderthal. Retrieved from
Stam, A. H., de Vries, B., Janssens, A. C., Vanmolkot, K. R., Aulchenko, Y. S., Henneman, P., . . . Terwindt, G. M. (2010). Shared genetic factors in migraine and depression: evidence from a genetic isolate. Neurology, 74, 288294.
Sullivan, P. F., Neale, M. C., & Kendler, K. S. (2000). Genetic epidemiology of major depression: Review and meta-analysis. American Journal of Psychiatry, 157, 15521562.
Svensson, D. A., Larsson, B., Waldenlind, E., & Pedersen, N. L. (2003). Shared rearing environment in migraine: Results from twins reared apart and twins reared together. Headache, 43, 235244.
Vos, T., Flaxman, A. D., Naghavi, M., Lozano, R., Michaud, C., Ezzati, M., . . . Memish, Z. A. (2012). Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: A systematic analysis for the global burden of disease study 2010. Lancet, 380, 21632196.
Wright, M. J., & Martin, N. G. (2004). Brisbane Adolescent Twin Study: Outline of study methods and research projects. Australian Journal of Psychology, 56, 6578.
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Twin Research and Human Genetics
  • ISSN: 1832-4274
  • EISSN: 1839-2628
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