Skip to main content

Gene–environment interplay in depressive symptoms: moderation by age, sex, and physical illness

  • A. J. Petkus (a1), C. R. Beam (a2), W. Johnson (a3), J. Kaprio (a4) (a5), T. Korhonen (a4) (a5) (a6), M. McGue (a7) (a8), J. M. Neiderhiser (a9), N. L. Pedersen (a10) (a11), C. A. Reynolds (a12), M. Gatz (a10) (a11) and for the IGEMS Consortium...

Numerous factors influence late-life depressive symptoms in adults, many not thoroughly characterized. We addressed whether genetic and environmental influences on depressive symptoms differed by age, sex, and physical illness.


The analysis sample included 24 436 twins aged 40–90 years drawn from the Interplay of Genes and Environment across Multiple Studies (IGEMS) Consortium. Biometric analyses tested age, sex, and physical illness moderation of genetic and environmental variance in depressive symptoms.


Women reported greater depressive symptoms than men. After age 60, there was an accelerating increase in depressive symptom scores with age, but this did not appreciably affect genetic and environmental variances. Overlap in genetic influences between physical illness and depressive symptoms was greater in men than in women. Additionally, in men extent of overlap was greater with worse physical illness (the genetic correlation ranged from near 0.00 for the least physical illness to nearly 0.60 with physical illness 2 s.d. above the mean). For men and women, the same environmental factors that influenced depressive symptoms also influenced physical illness.


Findings suggested that genetic factors play a larger part in the association between depressive symptoms and physical illness for men than for women. For both sexes, across all ages, physical illness may similarly trigger social and health limitations that contribute to depressive symptoms.

Corresponding author
*Address for correspondence: M. Gatz, Ph.D., Department of Psychology, University of Southern California, Los Angeles, CA 90089-1061, USA. (Email:
Hide All

Members of the IGEMS Consortium are given in the Appendix.

Hide All
Anttila V et al. (2016). Analysis of shared heritability in common disorders of the brain. bioRxiv. doi:10.1101/048991.
Berkman LF, Berkman CS, Kasl S, Freeman DH Jr., Leo L, Ostfeld AD, Cornoni-Huntley J, Brody J (1986). Depressive symptoms in relation to physical health and functioning in the elderly. American Journal of Epidemiology 124, 372388.
Bierut LJ, Heath AC, Bucholz KK, Dinwiddie SH, Madden PA, Statham DJ, Dunne MP, Martin NG (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.
Blazer DG (2003). Depression in late life: review and commentary. Journal of Gerontology Series A: Biological Sciences and Medical Sciences 58A, 249265.
Carmelli D, Swan GE, Kelly-Hayes M, Wolf PA, Reed T, Miller B (2000). Longitudinal changes in the contribution of genetic and environmental influences to symptoms of depression in older male twins. Psychology and Aging 15, 505510.
Christensen K, Holm NV, McGue M, Corder L, Vaupel JW (1999). A Danish population-based twin study on general health in the elderly. Journal of Aging and Health 11, 4964.
Djernes JK (2006). Prevalence and predictors of depression in populations of elderly: a review. Acta Psychiatrica Scandinavia 113, 372387.
Ehrlich BS, Isaacowitz DM (2002). Does subjective well-being increase with age? Perspectives in Psychology 5, 2026.
Finkel D, McGue M (1993). The origins of individual differences in memory among the elderly: a behavior genetic analysis. Psychology and Aging 8, 527537.
Finkel D, Pedersen NL (2004). Processing speed and longitudinal trajectories of change for cognitive abilities: The Swedish Adoption/Twin Study of Aging. Aging, Neuropsychology, and Cognition. Special Issue: Longitudinal Studies of Cognitive Aging 11, 325345.
Fiske A, Wetherell JL, Gatz M (2009). Depression in older adults. Annual Review of Clinical Psychology 5, 363389.
Forlani C, Morri M, Ferrari B, Dalmonte E, Menchetti M, De Ronchi D, Atti AR (2014). Prevalence and gender differences in late-life depression: a population-based study. American Journal of Geriatric Psychiatry 22, 370380.
Franz CE, Lyons MJ, O'Brien R, Panizzon MS, Kim K, Bhat R, Grant MD, Toomey R, Eisen S, Xian H, Kremen WS (2011). A 35-year longitudinal assessment of cognition and midlife depression symptoms: the Vietnam Era Twin study of aging. The American Journal of Geriatric Psychiatry 19, 559570.
Gatz M, Pedersen NL, Plomin R, Nesselroade JR, McClearn GE (1992). The importance of shared genes and shared environments for symptoms of depression in older adults. Journal of Abnormal Psychology 101, 701708.
Gatz M, Petkus A, Reynolds CA, Franz C, Kaprio J, Christensen K, for the IGEMS Consortium (2015 a). Age moderation of individual differences in chronic medical illness burden [Abstract]. Behavior Genetics 45, 657.
Gatz M, Reynolds CR, Finkel D, Hahn CJ, Zhou Y, Zavala C (2015b). Data harmonization in aging research: not so fast. Journal of Experimental Aging Research 41, 475495.
Gillespie NA, Kirk KM, Evans DM, Heath AC, Hickie IB, Martin NG (2004). Do the genetic or environmental determinants of anxiety and depression change with age? A longitudinal study of Australian twins. Twin Research 7, 3953.
Gold CH, Malmberg B, McClearn GE, Pedersen NL, Berg S (2002). Gender and health: a study of older unlike-sex twins. Journals of Gerontology: Series B: Psychological Sciences and Social Sciences 57B, S168S176.
Heath AC, Kessler RC, Neale MC, Hewitt JK, Eaves LJ, Kendler KS (1993). Testing hypotheses about direction of causation using cross sectional family data. Behavior Genetics 23, 2950.
Johnson W (2007). Genetic and environmental influences on behavior: capturing all the interplay. Psychological Review 114, 423440.
Johnson W, McGue M, Gaist D, Vaupel JW, Christensen K (2002). Frequency and heritability of depression symptomatology in the second half of life: evidence from Danish twins over 45. Psychological Medicine 32, 11751185.
Judd LL, Schettler PJ, Akiskal HS (2002). The prevalence, clinical relevance, and public health significance of subthreshold depressions. Psychiatric Clinics of North America 25, 685698.
Kaprio J (2013). The Finnish Twin Cohort Study: an update. Twin Research and Human Genetics 16, 157162.
Kaprio J, Koskenvuo M (2002). Genetic and environmental factors in complex diseases: the older Finnish Twin Cohort. Twin Research and Human Genetics 5, 358365.
Kendler KS, Gardner CO (2014). Sex differences in the pathways to Major Depression: a study of opposite-sex twin pairs. The American Journal of Psychiatry 171, 426435.
Kendler KS, Gardner CO, Neale MC, Prescott CA (2001). Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychological Medicine 4, 605616.
Kendler KS, Gatz M, Gardner CO, Pedersen NL (2006). A Swedish national twin study of lifetime major depression. American Journal of Psychiatry 163, 109114.
Kendler KS, Thornton LM, Gilman SE, Kessler RC (2000). Sexual orientation in a U.S. national sample of twin and nontwin sibling pairs. American Journal of Psychiatry 157, 18431846.
Kessler RC, Foster C, Webster PS, House JS (1992). The relationship between age and depressive symptoms in two national surveys. Psychology and Aging 7, 119126.
Korhonen T, Broms U, Varjonen J, Romanov K, Koskenvuo M, Kinnunen T, Kaprio J (2007). Smoking behaviour as a predictor for depression among Finnish men and women – a prospective study of adult twins. Psychological Medicine 37, 705715.
Kremen WS, Thompson-Brenner H, Leung YJ, Grant MD, Franz CE, Eisen SA, Jacobson KC, Boake C, Lyons MJ (2006). Genes, environment, and time: the Vietnam Era Twin Study of Aging (VETSA). Twin Research and Human Genetics 9, 10091022.
McArdle JJ, Hamagami F (2003). Structural equation models for evaluating dynamic concepts within longitudinal twin analyses. Behavioral Genetics 33, 137159.
McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA, Plomin R (1997). Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 276, 15601563.
McGue M, Christensen K (1997). Genetic and environmental contributions to depression symptomatology: evidence from Danish twins 75 years of age and older. Journal of Abnormal Psychology 106, 439448.
Meeks S, Murrell SA, Mehl RC (2000). Longitudinal relationships between depressive symptoms and health in normal older and middle-aged adults. Psychology and Aging 15, 100109.
Neale M, Hunter M, Pritikin JN, Zahery M, Brick TR, Kickpatrick RM, Estabrook R, Bates TC, Maes H, Boker SM (2016). Open Mx 2.0: extended structural equation and statistical modeling. Psychometrika 81, 535549.
Neale M, Roysamb E, Jacobson K (2006). Multivariate genetic analysis of sex limitation and GxE interaction. Twin Research and Human Genetics 9, 481489.
Neiderhiser JM, Lichtenstein P (2008). The Twin and Offspring Study in Sweden: advancing our understanding of genotype-environment interplay by studying twins and their families. Acta Psychologica Sinica 40, 11161123.
Pedersen NL, Christensen K, Dahl A, Finkel D, Franz C, Gatz M, Horwitz BN, Johansson B, Johnson W, Kremen WS, Lyons MJ, Malmberg B, McGue M, Neiderhiser JM, Peterson I, Reynolds CA (2013). IGEMS: The Consortium on Interplay of Genes and Environment across Multiple Studies. Twin Research and Human Genetics 16, 481489.
Radloff LS (1977). The CES – D scale: a self – report depressive mood scale for research in the general population. Applied Psychological Measurement 3, 385401.
Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goodard R (1986). CAMDEX: a standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry 149, 698709.
Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL, Morichi V, Spazzafumo L, Mancinelli L, Espinosa E, Rappelli A, Dessì-Fulgheri P (2008). A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. Journal of the American Geriatrics Society 56, 19261931.
SAS Institute Inc. (2013). SAS 9.4. SAS Institute Inc.: Cary, NC.
Schnittker J (2014). Natural Symptoms? The Intersection of Social, Biological, and Genetic Determinants of Depression in Later Life. Working paper: University of Pennsylvania Population, Aging Research Center. PARC Working Paper Series, WPS 14–01.
Scott KM, Lim C, Al-Hamzawi A, Alonso J, Bruffaerts R, Caldas-de-Almeida JM, Florescu S, de Girolamo G, Hu C, de Jonge P, Kawakami N, Medina-Mora ME, Moskalewicz J, Navarro-Mateu F, O'Neill S, Piazza M, Pasada-Villa J, Torres Y, Kessler RC (2016). Association of mental disorders with subsequent chronic physical conditions: world mental health surveys from 17 countries. JAMA Psychiatry 73, 150158.
Skytthe A, Christiansen L, Kyvik KO, Bødker FL, Hvidberg L, Petersen I, Nielsen MMF, Bingley P, Hjelmborg J, Tan Q, Holm NV, Vaupel JW, McGue M, Christensen K (2013). The Danish Twin Registry: linking surveys, national registers, and biological information. Twin Research and Human Genetics 16, 104111.
Sonnenberg CM, Beekman ATF, Deeg DJH, van Tilburg W (2000). Sex differences in late life depression. Acta Psychiatrica Scandinavica 101, 286292.
Steptoe A (2007). Depression and Physical Illness. Cambridge University Press: New York.
Sutin AR, Terracciano A, Milaneschi Y, An Y, Ferrucci L, Zonderman AB (2013). The trajectory of depressive symptoms across the adult lifespan. JAMA Psychiatry 70, 803811.
Takkinen S, Tolvanen A, Kaprio J, Berg S, Koskenvuo M, Rantanen T (2004). The genetic and environmental effects on depressive symptoms among older female twins. Twin Research 7, 626636.
Turkheimer E, Harden KP (2014). Behavior genetic research methods: testing quasi-causal hypotheses using multivariate twin data. In Handbook of Research Methods in Personality and Social Psychology (ed. Reis H. T. and Judd C. M.), pp. 159187. John Wiley: New York.
Twenge JM (2015). Time period and birth cohort differences in depressive symptoms in the U.S., 1982–2013. Social Indicators Research 121, 437454.
van der Sluis S, Posthuma D, Dolan CV (2012). A note on false positives and power in GxE modelling of twin data. Behavior Genetics 42, 170186.
Van Hulle C, Lahey B, Rathouz P (2013). Operating characteristics of alternative statistical methods for detecting gene-by-measured environment interaction in the presence of gene-environment correlation in twin and sibling studies. Behavior Genetics 43, 7184.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary materials

Petkus supplementary material
Petkus supplementary material

 Word (72 KB)
72 KB


Altmetric attention score

Full text views

Total number of HTML views: 18
Total number of PDF views: 144 *
Loading metrics...

Abstract views

Total abstract views: 655 *
Loading metrics...

* Views captured on Cambridge Core between 16th February 2017 - 20th January 2018. This data will be updated every 24 hours.