Variance Components Models for Gene–Environment Interaction in Twin Analysis
Open accessAbstract
Gene-environment interaction is likely to be a common and important source of variation for complex behavioral traits. Often conceptualized as the genetic control of sensitivity to the environment, it can be incorporated in variance components twin analyses by partitioning genetic effects into a mean part, which is independent of the environment, and a part that is a linear function of the environment. The model allows for one or more environmental moderator variables (that possibly interact with each other) that may i). be continuous or binary ii). differ between twins within a pair iii). interact with residual environmental as well as genetic effects iv) have nonlinear moderating properties v). show scalar (different magnitudes) or qualitative (different genes) interactions vi). be correlated with genetic effects acting upon the trait, to allow for a test of gene-environment interaction in the presence of gene-environment correlation. Aspects and applications of a class of models are explored by simulation, in the context of both individual differences twin analysis and, in a companion paper (Purcell & Sham, 2002) sibpair quantitative trait locus linkage analysis. As well as elucidating environmental pathways, consideration of gene-environment interaction in quantitative and molecular studies will potentially direct and enhance gene-mapping efforts.
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Phenotypes and continuous SES measures were Z-transformed prior to fitting the Purcell model to ensure effect sizes were on a comparable metric across studies.
“In order to ensure that effect sizes were placed on a metric that was comparable across studies, we ensured that phenotypes and continuous SES measures were Z-transformed (based on the M and SD from data pooled across all twins and siblings of all relatedness types) prior to fitting the Purcell (2002) model.”
From Large Cross-National Differences in Gene × Socioeconomic Status Interaction on Intelligence (2016) · cites this paper as Purcell (2002)
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BackgroundThe continuing value of twin studies in the omics era
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“4 To avoid bias in polynomial and interactive regression (of which nonlinear and interactive factor analysis is a general case), it is necessary to include the main effects of all variables that were multiplied to create higher order terms (Cohen, Cohen, West, & Aiken, 2003; Purcell, 2002).”
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“In other words, the effects of Gene Shared Environment interaction contribute to the estimate of genetic influence when not explicitly modeled (Purcell, 2002).”
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“Our estimates of the heritability for male and female twins can be considered an average heritability estimate across all levels of a particular environmental variable (Purcell, 2002).”
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“The publication of a paper the following year (Purcell 2002) that provided straightforward scripts for continuous gene-environment interaction models using the most widely used program for twin analyses, Mx (Neale 2000), led to a surge of papers studying geneenvironment interaction in the twin…”
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“Simulation studies of this model were provided by Purcell (2002), some recent empirical applications of the model in personality research can be seen in Johnson and Krueger (2005, 2006), and Johnson (2007) describes the broad relevance of this model for providing a richer understanding of how genes…”
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Genotype by Environment Interaction in Adolescents’ Cognitive Aptitude
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“Purcell (2002) demonstrated that inclusion of the main effect of the measured environment prevents bias in estimation of G × E interactions resulting from unspecified rGE.”
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“DISCUSSION Whereas ADHD carries well-established genetic influences on susceptibility (Waldman & Gizer, 2006), environmental risk factors may interact with that susceptibility in complex ways (Purcell, 2002).”
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“28 Two binary MDD outcomes were analysed as dependent variables: all participants with MDD v . controls (all MDD risk) and participants with severe MDD v . controls (severe MDD risk).”
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“This gene-environment interplay model (Figure 1) can be conceptualized as a bivariate extension of the univariate mode that incorporates additional moderation terms on the ACE effects.(38) This gene-environment interplay model estimates the ACE contributions to the covariance between externalizing and the environmenta…”
MethodResultSolving the missing heritability problem
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“Accordingly, future studies must build upon the present findings and incorporate gene-environment interaction and correlational models (Purcell, 2002) so as to delineate the mechanisms underlying stability and change in personality.”
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“Furthermore, since ADHD, like ASD, carries well-established genetic influences on susceptibility (Waldman & Gizer, 2006), it will be important to determine how lead may interact with that susceptibility (Purcell, 2002).”
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“This is the full model of the possible ways in which HI may be associated with HP (Purcell, 2002).”
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“In our final model, the effects of A, C, and E were allowed to vary as functions of SES (Purcell, 2002).”
Genetic and Environmental Contributions to Loneliness in Adults: The Netherlands Twin Register Study
Boomsma, D. I., Willemsen, G., Dolan, C. V., Hawkley, L. C., & Cacioppo, J. T. (2005) · Behavior Genetics · doi:10.1007/s10519-005-6040-8 · Cited by 191 · see citing works
“If there would be G C interaction, it would be part of the genetic variance in the twin model that was employed in this paper (Purcell, 2003), i.e. it is the genotype of the individual that determines the response to the common family environment.”
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Psychophysiological correlates of aggression and violence: an integrative review
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“Consequently, the consideration of an overall picture of the interplay between personality and environments needs more complex interactionist perspectives (South and Krueger 2008) and research strategies that requires large sample sizes such as modeling genotype– environment correlation in the presence of genotype– en…”
BackgroundUnderstanding the Early Origins of the Education–Health Gradient
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“Here, we discuss a binary environment, and we refer the reader to recent work by Purcell (2002) and Rathouz, Van Hulle, Rodgers, Waldman, and Lahey (2008) for the case of continuous figure we present E Y1 Y0½ E Y1jD ¼ 1½ E Y0jD ¼ 0½ .”
Teacher Quality Moderates the Genetic Effects on Early Reading
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Family dysfunction interacts with genes in the causation of antisocial symptoms
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“A model designed to test GE interaction of the latent genetic variable with a measured continuous moderator variable was used to test for gene-environment interaction (Fig. 1) ( Purcell, 2002 ).”
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“The second caveat is that the coefficient for unique environmental effects indexes not only the direct effects of unique experiences but also the effects of interactions between unique environments and genes (Purcell, 2002; Rutter and Silberg, 2002).”
BackgroundFamilial influences on basal salivary cortisol in an adult population.
Kupper, N., de Geus, E. D., van den Berg, M., Kirschbaum, C., Boomsma, D., & Willemsen, G. (2005) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.04.003 · Cited by 168 · see citing works
“Additionally, the correlations for DZ twins and siblings were not significantly different, indicating generalizability of twin study results to the general population.”
A pediatric twin study of brain morphometry.
Wallace, G. L., Schmitt, J. E., Lenroot, R., Viding, E., Ordaz, S. E., Rosenthal, M. A., Molloy, E. A., Clasen, L., Kendler, K., Neale, M., et al. (2006) · Journal of Child Psychology and Psychiatry and Allied Disciplines · doi:10.1111/j.1469-7610.2006.01676.x · Cited by 164 · see citing works
“Further, with the addition of individual-specific moderator variables, the standard ACE model can be expanded to account for interactions between A, C, and E with a second observed variable, such as age (Purcell, 2002).”
BackgroundSex differences in mental abilities: g masks the dimensions on which they lie
Johnson, W., & Bouchard, T. J. (2006) · Intelligence · doi:10.1016/j.intell.2006.03.012 · Cited by 167 · see citing works
“Correlation between genetic and shared environmental influences acts to increase estimates of shared environmental influence; correlation between genetic and nonshared environmental influences acts to increase estimates of genetic influence (Purcell, 2002).”
BackgroundParental Education Moderates Genetic Influences on Reading Disability
Friend, A., DeFries, J. C., & Olson, R. K. (2008) · Psychological Science · doi:10.1111/j.1467-9280.2008.02213.x · Cited by 156 · see citing works
“We also included the main effect of parental education in the DF regression test of the G E interaction to control for the influence of any gene-environment correlation on the G E interaction (Purcell, 2002).”
Etiology of Autism Spectrum Disorders and Autistic Traits Over Time
Taylor, M. J., Rosenqvist, M. A., Larsson, H., Gillberg, C., D'Onofrio, B. M., Lichtenstein, P., & Lundström, S. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.0680 · Cited by 198 · see citing works
“Such effects would be expected to inflate nonshared environmental variance components and produce changes in these components across birth cohorts.(44) However, our studydid showa small increase in themean level of and variance in autistic traits, specifically among individuals born between 2004 and 2008.”
Backgroundumx: Twin and Path-Based Structural Equation Modeling in R
Bates, T. C., Maes, H., & Neale, M. (2019) · Twin Research and Human Genetics · doi:10.1017/thg.2019.2 · Cited by 156 · see citing works
Changing Environmental Influences on Substance Use Across Development
Dick, D. M., Pagan, J. L., Viken, R. J., Purcell, S., Kaprio, J. A., Pulkkinen, L., & Rose, R. J. (2007) · Twin Research and Human Genetics · doi:10.1375/twin.10.2.315 · Cited by 146 · see citing works
“These models have subsequently been detailed and expanded [27].”
BackgroundMethodInfluentialSelf-citationFearon, R. M. P., Van IJzendoorn, M. H., Fonagy, P., Bakermans-Kranenburg, M. J., Schuengel, C., & Bokhorst, C. L. (2006) · Developmental Psychology · doi:10.1037/0012-1649.42.6.1026 · Cited by 153 · see citing works
“…test for background factors (e.g., gender, maternal age) that might moderate the genetic, shared environmental, and nonshared environmental effects on maternal sensitivity, we tested a set of nested structural models following methods developed by Purcell (2002) for continuous dependent variables.”
Feinberg, M. E., Button, T. M. M., Neiderhiser, J. M., Reiss, D., & Hetherington, E. M. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.4.457 · Cited by 153 · see citing works
“A focus on standardized components, as is typical in most behavior genetic reports, can lead to misinterpretation.(42) Because this point is important and underappreciated, we digress momentarily for an illustration: Consider in a hypothetical case that there are very low levels of variance in the phenotype at one lev…”
BackgroundIs There a “Party” in Your Genes?
Hatemi, P. K., Alford, J. R., Hibbing, J. R., Martin, N., & Eaves, L. (2009) · Political Research Quarterly · doi:10.1177/1065912908327606 · Cited by 154 · see citing works
“…have provided a productive initial platform for further research in medical, behavioral, and psychiatric genetics, including the study of gene–environment interaction (e.g., Purcell 2002 ) and the search for specific environmental factors and individual genes contributing to individual differences.”
BackgroundSubjective well-being: genetic and environmental contributions to stability and change
NES, R. B., Røysamb, E., TAMBS, K., HARRIS, J. R., & REICHBORN-KJENNERUD, T. (2006) · Psychological Medicine · doi:10.1017/s0033291706007409 · Cited by 214 · see citing works
“These mechanisms might bias parameter estimates in standard twin models and have to be taken into account when interpreting our results, as an interaction between A and E will act like E, and correlation between A and E will act like A (Purcell, 2002).”
BackgroundDick, D. M., Viken, R. J., Kaprio, J., Pulkkinen, L., & Rose, R. J. (2005) · Journal of Abnormal Child Psychology · doi:10.1007/s10802-005-1829-8 · Cited by 206 · see citing works
“New twin models allow for more explicit delineation of how genetic and environmental influences act and interact (Dick, Rose, Viken, Kaprio, & Koskenvuo, 2001; Purcell, 2002 ), and on-going analyses of the Finnish Twin data in this area clearly demonstrate the importance of gene‐environment interaction effects.”
BackgroundBleidorn, W., Kandler, C., & Caspi, A. (2014) · European Journal of Personality · doi:10.1002/per.1957 · Cited by 153 · see citing works
“Independent of GE correlation, G ×E interaction involving nonshared environmental influences on personality differences would have the effect of making genetically related individuals less similar to each other (Purcell, 2002).”
BackgroundYoung‐Wolff, K. C., Enoch, M., & Prescott, C. A. (2011) · Clinical Psychology Review · doi:10.1016/j.cpr.2011.03.005 · Cited by 157 · see citing works
“the twin model is expanded by including explicit measures of the environment or additional types of relatives, variance due to GxE can be separated from the variance due to latent genetic and environmental main effects (Purcell, 2002).”
BackgroundMethodInfluentialChildhood and Adolescent Anxiety and Depression: Beyond Heritability
Franić, S., Middeldorp, C. M., Dolan, C. V., Ligthart, L., & Boomsma, D. I. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.05.013 · Cited by 131 · see citing works
Rettew, D., Rebollo-Mesa, I., Hudziak, J., Willemsen, G., & Boomsma, D. (2008) · Behavior Genetics · doi:10.1007/s10519-008-9192-5 · Cited by 152 · see citing works
“In the genetic models, we estimated the influence of A, D, and E on extraversion and allowed these estimates to be a function of measured moderator variables age and sex (Purcell 2002).”
BackgroundSonuga‐Barke, E. J. S., Becker, S. P., Bölte, S., Castellanos, F. X., Franke, B., Newcorn, J. H., Nigg, J. T., Rohde, L. A., & Simonoff, E. (2023) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.13696 · Cited by 157 · see citing works
Changes in Genetic and Environmental Influences on Disordered Eating Across Adolescence
Klump, K. L., Burt, S. A., McGue, M. K., & Iacono, W. G. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.12.1409 · Cited by 133 · see citing works
“Gene-environment interactions are present when psychosocial risk factors have differential effects on disease outcome depending on the level of genetic risk.(23,24) Specifically, individuals with genetic predispositions are at increased risk for a disorder when environmental risk factors are present.”
BackgroundA Note on False Positives and Power in G × E Modelling of Twin Data
van der Sluis, S., Posthuma, D., & Dolan, C. (2011) · Behavior Genetics · doi:10.1007/s10519-011-9480-3 · Cited by 149 · see citing works
Cai, N., Choi, K. W., & Fried, E. I. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa115 · Cited by 153 · see citing works
“GXE effects detected between PRS and environmental contexts could therefore differ accordingly (78,79).”
BackgroundGenetic Epidemiology of Attention Deficit Hyperactivity Disorder (ADHD Index) in Adults
Boomsma, D. I., Saviouk, V., Hottenga, J.-J., Distel, M. A., de Moor, M. H. M., Vink, J. M., Geels, L. M., van Beek, J. H. D. A., Bartels, M., de Geus, E. J. C., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010621 · Cited by 140 · see citing works
“to unique environment, and thus decrease estimates of heritability [29,30].”
BackgroundThe heritability of self-control: A meta-analysis
Willems, Y. E., Boesen, N., Li, J., Finkenauer, C., & Bartels, M. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.02.012 · Cited by 168 · see citing works
Genetic confounding of the relationship between father absence and age at menarche
Barbaro, N., Boutwell, B. B., Barnes, J. C., & Shackelford, T. K. (2016) · Evolution and Human Behavior · doi:10.1016/j.evolhumbehav.2016.11.007 · Cited by 148 · see citing works
Political Science, Biometric Theory, and Twin Studies: A Methodological Introduction
Medland, S. E., & Hatemi, P. (2009) · Political Analysis · doi:10.1093/pan/mpn016 · Cited by 134 · see citing works
“…the sum and absolute differences of data from MZ co-twins (i.e., heteroscedasticity) (Jinks and Fulker 1970; van der Sluis et al. 2006) or by partitioning the variance components into that which is linked to variation within the environmental influence and that which is residual (see Purcell 2002).”
BackgroundSources of cumulative continuity in personality: A longitudinal multiple-rater twin study.
Kandler, C., Bleidorn, W., Riemann, R., Spinath, F. M., Thiel, W., & Angleitner, A. (2010) · Journal of Personality and Social Psychology · doi:10.1037/a0019558 · Cited by 141 · see citing works
Nature and nurture of the interplay between personality traits and major life goals.
Bleidorn, W., Kandler, C., Hulsheger, U. R., Riemann, R., Angleitner, A., & Spinath, F. M. (2010) · Journal of Personality and Social Psychology · doi:10.1037/a0019982 · Cited by 163 · see citing works
Gestational diabetes hinders language development in offspring
Dionne, G., Boivin, M., Séguin, J. R., Pérusse, D., & Tremblay, R. E. (2008) · Pediatrics · doi:10.1542/peds.2007-3028 · Cited by 136 · see citing works
“000 University degree 25 (24) 19 (16) 44 (20) 486 (28) 296 (34) 782 (30) Poverty, n (%) 22 (21) 29 (25) 51 (23) 378 (22) 121 (14) 499 (19) .”
Sauce, B., & Matzel, L. D. (2017) · Psychological Bulletin · doi:10.1037/bul0000131 · Cited by 172 · see citing works
“Or as elegantly pointed out by (Purcell, 2002), “G×E is often conceptualized as genetic control of sensitivity to different environments.”
Duncan, L. E., Pollastri, A. R., & Smoller, J. W. (2014) · American Psychologist · doi:10.1037/a0036320 · Cited by 137 · see citing works
“E contributes to the additive genetic (h2, narrow-sense heritability) or nonshared environmental variance component in twin models (Purcell, 2002), so it is unclear whether—on balance—”
BackgroundThe Genetics of Substance Use and Substance Use Disorders
Dick, D. M., Prescott, C. A., & McGue, M. K. (2009) · Springer eBooks · doi:10.1007/978-0-387-76727-7_29 · Cited by 131 · see citing works
Blonigen, D. M. (2009) · Clinical Psychology Review · doi:10.1016/j.cpr.2009.10.001 · Cited by 136 · see citing works
“Recent advances in behavioral genetic methodology offer a promising avenue for disentangling the etiological relations among these constructs by testing for both gene–environment interactions (G×E) and gene–environment correlations (rGE) within the same model (Purcell, 2002).”
Genetic influences on thinning of the cerebral cortex during development
van Soelen, I. L. C., Brouwer, R. M., van Baal, G. C. M., Schnack, H. G., Peper, J. S., Collins, D. L., Evans, A. C., Kahn, R. S., Boomsma, D. I., & Pol, H. E. H. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.11.044 · Cited by 94 · see citing works
“The effects of GE correlation also depend on whether E consists of unique or common environmental influences: correlation between G and C acts like C (which we did not detect); correlation between G and E acts like G (Purcell, 2002) and thus could be included in the total heritability.”
BackgroundLife events, anxious depression and personality: a prospective and genetic study
Middeldorp, C. M., Cath, D. C., Beem, A. L., Willemsen, G. A. H. M., & Boomsma, D. I. (2008) · Psychological Medicine · doi:10.1017/s0033291708002985 · Cited by 114 · see citing works
“A significant gene–environment interaction effect can be due to gene–environment correlation if this correlation is not included in the model (Purcell, 2002).”
BackgroundIs the Effect of Parental Education on Offspring Biased or Moderated by Genotype?
Conley, D., Domingue, B. W., Cesarini, D. A., Dawes, C. T., Rietveld, C. A., & Boardman, J. (2015) · Sociological Science · doi:10.15195/v2.a6 · Cited by 145 · see citing works
“…a wide range of social and behavioral scientists, despite the controversy surrounding such estimates (e.g., see Breen, Plomin, and Wardle 2006; Plomin, Owen, and McGuffin 1994, 1997; Plomin and Spinath 2004; Plomin 2009; Purcell 2002; Rodgers, Rowe, and Buster 1999; Rodgers, Buster, and Rowe 2001).”
BackgroundKlump, K., & Burt, S. (2006) · Twin Research and Human Genetics · doi:10.1375/twin.9.6.971 · Cited by 126 · see citing works
“…examine genetic and environmental contributions to antisocial behavior and disordered eating, (2) perform genetic association studies, and (3) examine gene–environment interplay, using both biometric models (Purcell, 2002) and measured-gene × measured-environment analyses (Moffitt et al., 2005).”
Peyrot, W. J., der Auwera, S. V., Milaneschi, Y., Dolan, C. V., Madden, P. A. F., Sullivan, P. F., Strohmaier, J., Ripke, S., Rietschel, M., Nivard, M. G., et al. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.09.009 · Cited by 122 · see citing works
“Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009): Common 504 polygenic variation contributes to risk of schizophrenia and bipolar disorder.”
InfluentialConley, D., Rauscher, E. A., Dawes, C. T., Magnusson, P., & Siegal, M. L. (2013) · Behavior Genetics · doi:10.1007/s10519-013-9602-1 · Cited by 123 · see citing works
“Likewise, non-linear interactions between alleles—such as dominance—have been modeled in attempts to get at broad-sense heritability (H2) (see Purcell 2002 for a review of these models and simulation exercises and Purcell and Sham 2002 for an empirical example).”
- Authors
- Purcell, S.
- Affiliations
- King's College London (GB)
- Corresponding author
- Purcell, Shaun
- ORCID
- Purcell, Shaun
- Venue
- Twin Research
- Publisher
- Cambridge University Press (CUP)
- Published
- 2002-12-01
- Volume
- 5
- Issue
- 6
- Pages
- 554-571
- ISSN
- 1369-0523 (ISSN-L)
- 0000-0000
- OpenAlex
- W2052208159
- Cited by
- 924
- References
- 0
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 27 · 2023: 39 · 2022: 52 · 2021: 40 · 2020: 50 · 2019: 36 · 2018: 37 · 2017: 54 · 2016: 49 · 2015: 60 · 2014: 56 · 2013: 46 · 2012: 45
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Twin Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- National Eye Institute (EY12562, R01EY012562)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Assisted Reproductive Technology and Twin Pregnancy
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
- Keywords
- gene-environment interaction, variance component models, gene-environment correlation, environmental moderators, individual differences, quantitative trait loci, gene mapping, nonlinear interactions, environmental pathways
- MeSH terms
- Computer Simulation, Environment, Genetics, Behavioral, Humans, Models, Genetic, Twins
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