CP07CH15-Dick ARI 9 March 2011 21:44 Gene-Environment Interaction in Psychological Traits and Disorders Danielle M. Dick Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298-0126; email: [email protected] Annu. Rev. Clin. Psychol. 2011. 7:383–409 Keywords First published online as a Review in Advance on genetics, association, review, GxE, psychopathology January 6, 2011 The Annual Review of Clinical Psychology is online Abstract at clinpsy.annualreviews.org There has been an explosion of interest in studying gene-environment This article’s doi: interactions (GxE) as they relate to the development of psychopathol- 10.1146/annurev-clinpsy-032210-104518 ogy. In this article, I review different methodologies to study Copyright c 2011 by Annual Reviews. gene-environment interaction, providing an overview of methods from by State University of New York - Brooklyn on 01/23/12. For personal use only. All rights reserved animal and human studies and illustrations of gene-environment inter- Annu. Rev. Clin. Psychol. 2011.7:383-409. Downloaded from www.annualreviews.org 1548-5943/11/0427-0383$20.00 actions detected using these various methodologies. Gene-environment interaction studies that examine genetic influences as modeled latently (e.g., from family, twin, and adoption studies) are covered, as well as studies of measured genotypes. Importantly, the explosion of interest in gene-environment interactions has raised a number of challenges, including difficulties with differentiating various types of interactions, power, and the scaling of environmental measures, which have profound implications for detecting gene-environment interactions. Taking research on gene-environment interactions to the next level will necessitate close collaborations between psychologists and geneticists so that each field can take advantage of the knowledge base of the other. 383 CP07CH15-Dick ARI 9 March 2011 21:44 merging of interests from fields that were tradi- Contents tionally at odds with one another. Historically, there was a perception that behavior geneticists INTRODUCTION.................. 384 focused on genetic influences on behavior at the DEFINING expense of studying environmental influences GENE-ENVIRONMENT and that developmental psychologists focused INTERACTION AND on environmental influences and largely ig- DIFFERENTIATING nored genetic factors. Although this criticism is GENE-ENVIRONMENT not entirely founded on the part of either field, CORRELATION................. 385 methodological and ideological differences be- METHODS FOR STUDYING tween these respective fields meant that genetic GENE-ENVIRONMENT and environmental influences were tradition- INTERACTION.................. 386 ally studied in isolation. More recently, there AnimalResearch................... 386 has been recognition on the part of both of HumanResearch.................. 387 these fields that both genetic and environmental THENATUREOF influences are critical components to develop- GENE-ENVIRONMENT mental outcome and that it is far more fruitful to INTERACTION.................. 393 attempt to understand how these factors come EPIGENETICS: A POTENTIAL together to impact psychological outcomes BIOLOGICAL MECHANISM than to argue about which one is more im- FOR GENE-ENVIRONMENT portant. As Kendler and Eaves argued in their INTERACTION.................. 397 article on the joint effect of genes and environ- CONCLUSIONS.................... 399 ments, published more than two decades ago: Knowledge Is Power . 399 Use What We Already Know from It is our conviction that a complete under- the Twin and Developmental standing of the etiology of most psychiatric Literatures..................... 399 disorders will require an understanding of Statistics Are Not a Substitute the relevant genetic risk factors, the relevant forCriticalThinking............ 401 environmental risk factors, and the ways in Play Nice in the Sandbox . 401 which these two risk factors interact. Such un- derstanding will only arise from research in which the important environmental variables are measured in a genetically informative de- sign. Such research will require a synthesis of INTRODUCTION research traditions within psychiatry that have by State University of New York - Brooklyn on 01/23/12. For personal use only. Gene-environment interaction (GxE) has be- often been at odds with one another in the Annu. Rev. Clin. Psychol. 2011.7:383-409. Downloaded from www.annualreviews.org come a hot topic of research, with an expo- past. This interaction between the research nential increase in interest in this area in the tradition that has focused on the genetic eti- past decade. Consider that PubMed lists only ology of psychiatric illness and that which has 24 citations for “gene environment interaction” emphasized environmental causation will un- prior to the year 2000, but nearly four times doubtedly be to the benefit of both. (Kendler Gene: unit of that many in the first half of the year 2010 & Eaves 1986, p. 288) heredity; a stretch of alone! The projected publications on gene- DNA that codes for a protein environment interaction for 2008–2010 are on The PubMed data showing an expo- track to constitute more than 40% of the total nential increase in published papers on GxE: gene- environment number of publications on gene-environment gene-environment interaction suggest that interaction interaction indexed in PubMed. Where does all that day has arrived. This has been facilitated this interest stem from? It may, in part, reflect a by the rapid advances that have taken place in 384 Dick CP07CH15-Dick ARI 9 March 2011 21:44 the field of genetics, making the incorporation a potential biological mechanism by which the of genetic components into traditional psycho- environment can moderate gene expression logical studies a relatively easy and inexpensive and affect behavior. Finally, I conclude with Epigenetics: endeavor. But with this surge of interest in recommendations for future directions and modifications to the gene-environment interaction, a number of how we can take research on gene-environment genome that do not new complications have emerged, and the interaction to the next level. involve a change in study of gene-environment interaction faces nucleotide sequence new challenges, including a recent backlash against studying gene-environment interaction DEFINING (Risch et al. 2009). Addressing these chal- GENE-ENVIRONMENT lenges will be critical to moving research on INTERACTION AND gene-environment interaction forward in a DIFFERENTIATING productive way. GENE-ENVIRONMENT In this article, I first review different CORRELATION study designs for detecting gene-environment It is important to first address some aspects interaction, providing an overview of methods of terminology surrounding the study of gene- from animal and human studies. I cover environment interaction. In lay terms, the gene-environment interaction studies that phrase gene-environment interaction is often examine genetic influences as modeled latently used to mean that both genes and environments as well as studies of measured genotypes. In the are important. In statistical terms, this does not study of latent gene-environment interaction, necessarily indicate an interaction but could specific genotypes are not measured, but be consistent with an additive model, in which rather genetic influence is inferred based there are main effects of the environment and on observed correlations between people main effects of genes. But in a statistical sense an who have different degrees of genetic and interaction is a very specific thing, referring to a environmental sharing. Thus, latent gene- situation in which the effect of one variable can- environment interaction studies examine the not be understood without taking into account aggregate effects of genes rather than any one the other variable. Their effects are not inde- specific gene. Molecular genetic studies, in pendent. When we refer to gene-environment contrast, have generally focused on one specific interaction in a statistical sense, we are refer- gene of interest at a time. Relevant examples ring to a situation in which the effect of genes of gene-environment interaction across these depends on the environment and/or the effect different methodologies are provided, though of the environment depends on genotype. We these are meant to be more illustrative than note that these two alternative conceptualiza- exhaustive, intended to introduce the reader to tions of gene-environment interaction are in- by State University of New York - Brooklyn on 01/23/12. For personal use only. relevant studies and findings generated across distinguishable statistically. It is this statistical Annu. Rev. Clin. Psychol. 2011.7:383-409. Downloaded from www.annualreviews.org these various designs. Subsequently I review definition of gene-environment interaction that more conceptual issues surrounding the study is the primary focus of this review (except where of gene-environment interaction, covering otherwise noted). the nature of gene-environment interaction It is also important to note that genetic effects as well as the challenges facing the and environmental influences are not neces- study of gene-environment interaction, such as sarily independent factors. That is to say that difficulties with differentiating various types of although some environmental influences may interactions, and how issues such as the scaling be largely random, such as experiencing