Skip to main content Accessibility help

Epigenome-Wide Association Study of Wellbeing

  • Bart M. L. Baselmans (a1) (a2), Jenny van Dongen (a1) (a2), Michel G. Nivard (a1), Bochao D. Lin (a1), BIOS Consortium (a3), Nuno R. Zilhão (a1), Dorret I. Boomsma (a1) (a2) (a4) and Meike Bartels (a1) (a2) (a4)...


Wellbeing (WB) is a major topic of research across several scientific disciplines, partly driven by its strong association with psychological and mental health. Twin-family studies have found that both genotype and environment play an important role in explaining the variance in WB. Epigenetic mechanisms, such as DNA methylation, regulate gene expression, and may mediate genetic and environmental effects on WB. Here, for the first time, we apply an epigenome-wide association study (EWAS) approach to identify differentially methylated sites associated with individual differences in WB. Subjects were part of the longitudinal survey studies of the Netherlands Twin Register (NTR) and participated in the NTR biobank project between 2002 and 2011. WB was assessed by a short inventory that measures satisfaction with life (SAT). DNA methylation was measured in whole blood by the Illumina Infinium HumanMethylation450 BeadChip (HM450k array) and the association between WB and DNA methylation level was tested at 411,169 autosomal sites. Two sites (cg10845147, p = 1.51 * 10−8 and cg01940273, p = 2.34 * 10−8) reached genome-wide significance following Bonferonni correction. Four more sites (cg03329539, p = 2.76* 10−7; cg09716613, p = 3.23 * 10−7; cg04387347, p = 3.95 * 10−7; and cg02290168, p = 5.23 * 10−7) were considered to be genome-wide significant when applying the widely used criterion of a FDR q value < 0.05. Gene ontology (GO) analysis highlighted enrichment of several central nervous system categories among higher-ranking methylation sites. Overall, these results provide a first insight into the epigenetic mechanisms associated with WB and lay the foundations for future work aiming to unravel the biological mechanisms underlying a complex trait like WB.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Epigenome-Wide Association Study of Wellbeing
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Epigenome-Wide Association Study of Wellbeing
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Epigenome-Wide Association Study of Wellbeing
      Available formats


Corresponding author

address for correspondence: Bart Baselmans, Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, 1081BT, Amsterdam, the Netherlands. E-mail:


Hide All
Allione, A., Marcon, F., Fiorito, G., & Guarrera, S. (2015). Novel epigenetic changes unveiled by monozygotic twins discordant for smoking habits. PloS One, 10, e0128265.
Artavanis-tsakonas, S., Rand, M. D., & Lake, R. J. (1999). Notch signaling: Cell fate control and signal integration in development. Science, 284, 770777.
Bartels, M. (2015). Genetics of happiness, satisfaction with life, and wellbeing; A review and meta-analysis of heritability studies. Behavior Genetics, 45, 137156.
Bartels, M., & Boomsma, D. I. (2009). Born to be happy? The etiology of subjective well-being. Behavior Genetics, 39, 605615.
Bartels, M., Cacioppo, J. T., van Beijsterveldt, T. C., & Boomsma, D. I. (2013). Exploring the association between well-being and psychopathology in adolescents. Behavior Genetics, 43, 177190.
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological), 57 (1), 289300.
Bernstein, B. E., Meissner, A., & Lander, E. S. (2007). The mammalian epigenome. Cell, 128, 669681.
Bibikova, M., Barnes, B., Tsan, C., Ho, V., Klotzle, B., Le, J. M., . . . Shen, R. (2011). High density DNA methylation array with single CpG site resolution. Genomics, 98, 288295.
Blanchflower, D. G., & Oswald, A. J. (2008). Is well-being U-shaped over the life cycle? Social Science & Medicine, 66, 17331749.
Brock, D. J., & Barron, L. (1988). Measurement of placental alkaline phosphatase in maternal plasma as an indicator of subsequent low birthweight outcome. Journal of Obstetrics & Gynaecology, 95, 7983.
Chen, Y. A., Lemire, M., Choufani, S., Butcher, D. T., Grafodatskaya, D., Zanke, B. W., . . . Weksberg, R. (2013). Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics, 8, 203209.
Dalton, V. S., Kolshus, E., & McLoughlin, D. M. (2014). Epigenetics and depression: Return of the repressed. Journal of Affective Disorders, 155, 112.
Dempster, E. L., Wong, C. C. Y., Lester, K. J., Burrage, J., Gregory, A. M., Mill, J., & Eley, T. C. (2014). Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biological Psychiatry, 76, 977983.
Diener, E. D., Emmons, R. A., Larsen, R. J., & Griffin, S. (1985). The Satisfaction With Life Scale. Journal of Personality Assessment, 49, 7175.
Dominguez-salas, P., Moore, S. E., Baker, M. S., Bergen, A. W., Cox, S. E., Dyer, R. A., . . . Hennig, B. J. (2014). Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nature Communications, 5, 17.
Dontu, G., Jackson, K. W., McNicholas, E., Kawamura, M. J., Abdallah, W. M., & Wicha, M. S. (2004). Research article role of notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Research, 6, 605615.
Eden, E., Navon, R., Steinfeld, I., Lipson, D., & Yakhini, Z. (2009). GOrilla: A tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics, 10, 48.
Fortin, J. (2014). Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biology, 15, 503.
Fujita, F., & Diener, E. D. (2005). Life satisfaction set point: Stability and change. Journal of Personality and Social Psychology, 88, 158164.
Genome of the Netherlands Consortium. (2014). Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nature Genetics, 46, 818825.
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, D. (2002). The human genome browser at UCSC. Genome Research, 12, 9961006.
Kleinschmidt, A., Klopp, N., Zeilinger, S., Ku, B., Gieger, C., Weidinger, S., . . . Illig, T. (2013). Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One, 8, e63812.
Klengel, T., Pape, J., & Binder, E. B. (2014). The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology, 80, 115132.
Koshida, K., Stigbrand, T., Hisazumi, H., & Wahren, B. (1990). Analysis of serum placental alkaline phosphatase activity in testicular cancer and cigarette smokers. Urological Research, 18, 169173.
Koshida, K., Uchibayashi, T., Yamamoto, H., & Hirano, K. (1996). Significance of placental alkaline phosphatase (PLAP) in the monitoring of patients with seminoma. British Journal of Urology, 77, 138142.
Layard, R. (2010). Measuring subjective well-being. Science, 327, 534535.
Lee, K. W. K., Richmond, R., Hu, P., French, L., Shin, J., Bourdon, C., & Reischl, E. (2015). Prenatal exposure to maternal cigarette smoking and dna methylation: Epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environmental Health Perspectives, 123, 193199.
Meyer, R. E., Thompson, S. J., Addy, C. L., Garrison, C. Z., & Best, R. G. (1995). Maternal serum placental alkaline phosphatase level and risk for preterm delivery. American Journal of Obstetrics & Gynecology, 173, 181186.
Miele, L., & Osborne, B. (1999). Arbiter of differentiation and death: Notch signaling meets apoptosis. Journal of Cellular Physiology, 409, 393409.
Oh, G., Wang, S. C., Pal, M., Chen, Z. F., Khare, T., Tochigi, M., . . . Petronis, A. (2015). DNA modification study of major depressive disorder: Beyond locus-by-locus comparisons. Biological Psychiatry, 77, 246255.
Philibert, R., Hollenbeck, N., Andersen, E., Osborn, T., Gerrard, M., Gibbons, F. X., & Wang, K. (2015). A quantitative epigenetic approach for the assessment of cigarette consumption. Frontiers in Psychology, 6, 18.
Piper, M. E., Kenford, S., Fiore, M. C., & Baker, T. B. (2012). Smoking cessation and quality of life: Changes in life satisfaction over 3 years following a quit attempt. Annals of Behavioral Medicine, 43, 262270.
Rakyan, V. K., Down, T. A., Balding, D. J., & Beck, S. (2011). Epigenome-wide association studies for common human diseases. Nature Reviews. Genetics, 12, 529541.
Reik, W. (2007). Stability and flexibility of epigenetic gene regulation in mammalian development. Nature, 447, 425432.
Romens, S. E., McDonald, J., Svaren, J., & Pollak, S. D. (2015). Associations between early life stress and gene methylation in children. Child Development, 86, 303309.
Seaford, C. (2011). Policy: Time to legislate for the good life. Nature, 477, 532533.
Shahab, L., & West, R. (2012). Differences in happiness between smokers, ex-smokers and never smokers: Cross-sectional findings from a national household survey. Drug and Alcohol Dependence, 121, 3844.
Slieker, R. C., Bos, S. D., Goeman, J. J., Bovée, J. V., Talens, R. P., van der Breggen, R., . . . Heijmans, B. T. (2013). Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array. Epigenetics & Chromatin, 6, 26.
Steptoe, A., Deaton, A., & Stone, A. A. (2014). Subjective wellbeing, health, and ageing. The Lancet, 385, 640648.
Stiglitz, J. E., Sen, A., & Fitoussi, J. P. (2009). Report by the commission on the measurement of economic performance and social progress. Issaquah, WA: Community Indicators Consortium. Retrieved from
Stubbe, J. H., Posthuma, D., Boomsma, D. I., & De Geus, E. J. (2005). Heritability of life satisfaction in adults: A twin-family study. Psychological Medicine, 35, 15811588.
The ENCODE project Consortium. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 5774.
Tsaprouni, L. G., Yang, T. P., Bell, J., Dick, K. J., Kanoni, S., Nisbet, J., & Deloukas, P. (2014). Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation. Epigenetics, 9, 13821396.
Van Beijsterveldt, C. E. M., Groen-Blokhuis, M., Hottenga, J. J., Franić, S., Hudziak, J. J., Lamb, D., . . . Boomsma, D. I. (2013). The young Netherlands twin register (YNTR): Longitudinal twin and family studies in over 70,000 children. Twin Research and Human Genetics, 16, 252267.
Van Dongen, J., Nivard, M. G., Baselmans, B. M. L., Zilhão, N. R., Ligthart, L., Bios Consortium, . . . Boomsma, D. I. (2015). Epigenome-wide association study of aggressive behavior. Twin Research and Human Genetics, 18, 113.
Van Dongen, J., Nivard, M. G., Willemsen, A. H. M., Hottenga, J. J., Helmer, Q., Dolan, C. V., . . . Boomsma, D. I. (2015). Genetic and environmental influences interact with age and sex in shaping the human methylome. Manuscript submitted for publication.
Van Iterson, M., Tobi, E. W., Slieker, R. C., den Hollander, W., Luijk, R., Slagboom, P. E., & Heijmans, B. T. (2014). MethylAid: Visual and interactive quality control of large Illumina 450k datasets, Bioinformatics, 30, 34353437.
Willemsen, G., de Geus, E. J. C., Bartels, M., van Beijsterveldt, C. E. M. T., Brooks, A. I., Estourgie-van Burk, G. F., . . . Boomsma, D. I. (2010). The Netherlands Twin Register biobank: A resource for genetic epidemiological studies. Twin Research and Human Genetics, 13, 231245.
Willemsen, G., Vink, J. M., Abdellaoui, A., den Braber, A., van Beek, J. H., Draisma, H. H., . . . Boomsma, D. I. (2013). The adult Netherlands twin register: Twenty-five years of survey and biological data collection. Twin Research and Human Genetics, 16, 271281.
Wilson, D., Parsons, J., & Wakefield, M. (1999). The health-related quality-of-life of never smokers, ex-smokers, and light, moderate, and heavy smokers. Preventive Medicine, 29, 139144.
Recommend this journal

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

Twin Research and Human Genetics
  • ISSN: 1832-4274
  • EISSN: 1839-2628
  • URL: /core/journals/twin-research-and-human-genetics
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary materials

Baselmans supplementary material
Table S1

 Excel (15 KB)
15 KB
Supplementary materials

Baselmans supplementary material
Table S2

 Excel (10 KB)
10 KB
Supplementary materials

Baselmans supplementary material
Table S3

 Excel (1.1 MB)
1.1 MB
Supplementary materials

Baselmans supplementary material
Table S4

 Excel (34 KB)
34 KB
Supplementary materials

Baselmans supplementary material
Baselmans supplementary material 1

 Word (227 KB)
227 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed