Gene-environment Interplay Research Articles

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition.

Although autism spectrum condition (ASC) is strongly genetic in origin, accumulating evidence points to the critical roles of various environmental influences on its emergence and subsequent developmental course. A developmental psychopathology framework was used to synthesise literature on environmental factors associated with the onset and course of ASC (based on a systematic search of the literature using PubMed, PsychInfo and Google Scholar databases). Particular emphasis was placed on gene-environment interplay, including gene-environment interaction (G × E) and gene-environment correlation (rGE). Before conception, advanced paternal and maternal ages may independently enhance offspring risk for ASC. Exogenous prenatal risks are evident (e.g. valproate and toxic chemicals) or possible (e.g. selective serotonin reuptake inhibitors), and processes endogenous to the materno-foeto-placental unit (e.g. maternal diabetes, enhanced steroidogenic activities and maternal immune activation) likely heighten offspring vulnerability to ASC. Folate intake is a prenatal protective factor, with a particular window of action around 4 weeks preconception and during the first trimester. These prenatal risks and protective mechanisms appear to involve G × E and potentially rGE. A variety of perinatal risks are related to offspring ASC risk, possibly reflecting rGE. Postnatal social factors (e.g. caregiver-infant interaction, severe early deprivation) during the first years of life may operate through rGE to influence the likelihood of manifesting a full ASC phenotype from a 'prodromal' phase (a proposal distinct to the discredited and harmful 'refrigerator mother hypothesis'); and later postnatal risks, after the full manifestation of ASC, shape life span development through transactions mediated by rGE. There is no evidence that vaccination is a postnatal risk for ASC. Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene-environment interplay, large-sample genome-envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed.

Parkinson’s Disease: New Insights into Pathophysiology and Rehabilitative Approaches

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder, but up till now, its etiology remains largely unknown. Progressive impairment of voluntary motor control, which represents the primary clinical feature of the disease, is caused by a loss of midbrain substantia nigra dopamine (DA) neurons. PD prevalence increases steadily with age. Therefore, with the aging population, we will see an increase in social and health impact of this disease. Currently, the drugs available improve physical performances and lengthen life expectancy and autonomy in the activities of daily living by reducing adverse events; it follows that they improve the quality of life of patients. However, these drugs are symptomatic and not curative. When the patient reaches the maximum allowable therapeutic dosage of levodopa, we have to face great difficulties and impotence in disease's management. Recently, the role of rehabilitation in the field of neurodegenerative diseases is becoming more and more important as it results from several studies. In this special issue, we wanted to focus our attention on the “holistic view” of the disease because we believe that only a multidisciplinary approach could help to face it in the best way. PD involves miscellaneous systems (physical, mental, and behavioral structures) affecting also the autonomy in self-care management. Furthermore, in this special issue we wanted to draw the attention to the importance of rehabilitation in PD. An amount of epidemiological evidence stressed the importance of the relationships between genetic and environmental factors. L. Polito et al. summarize evidence on gene-environment interplay in the development of PD focusing on susceptibility factors and causal genetic mutation. To the best of our knowledge, this review is the first attempt to analyze all those genetic factors that modify the impact of environmental exposure. Brilliantly, F. Magrinelli et al. contributed to examining the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD, with particular attention to those clinical features that impair quality of life and functional ability of patients. Starting from anatomic basis of the main circuit involved in PD, subsequently they analyzed the pathophysiology of PD motor symptoms (bradykinesia and tremor rigidity) and signs (postural balance, gait impairment, fatigue, and pain). Currently, pharmacological treatment of motor symptoms of PD depends mainly on the administration of dopaminergic drugs (levodopa and dopamine agonists) and other drugs involved in levodopa metabolism (monoamine oxidase-B inhibitors and catechol-O-methyltransferase inhibitors). Usually, in the late disease stages, PD patients treated by dopaminergic drugs display various complications, such as on-off fluctuations of Parkinsonian symptoms and dyskinesia. Unfortunately, most patients with advanced PD are unsatisfactorily controlled by the usual therapeutic approach. A. Daniele et al. examine other pharmacological targets regardless of the dopaminergic pathway. In particular, they focus on potential beneficial effects of zolpidem, a positive allosteric modulator of GABAA receptors, on the motor symptoms of PD. In fact, some studies have previously suggested that there is a high density of zolpidem binding sites in the globus pallidus and in the substantia nigra, which are the output structures of the basal ganglia. Two experimental works complete this brief special issue. The first is a case control study carried out by M. Tramontano et al. with the aim of investigating the efficacy of a blindfolded balance training in the improvement of gait parameters in people with PD compared to patients who underwent a standard physical therapy program. The second is a prospective open-label feasibility study evaluating the impact of 8-week action observation training (video-therapy) for the treatment of postural instability and balance impairment in PD patients. Although in this latter study A. Santamato et al. did not find positive results, they underline one of the most important shortcomings in PD rehabilitation field. In fact, absence of standard procedures to improve balance and posture in PD subjects makes this area a virgin field to explore. We hope that the contents of this special issue may help clinicians better understand the rationale of current pharmacological and rehabilitation strategies for PD and give viability to further studies that integrate current knowledge with innovations in the field of rehabilitation. Vincenza Frisardi Andrea Santamato Binith Cheeran

A Primer on the Genetics of Comorbid Eating Disorders and Substance Use Disorders.

Eating disorders (EDs) and substance use disorders (SUDs) frequently co-occur; however, the reasons for this are unclear. We review the current literature on genetic risk for EDs and SUDs, as well as preliminary findings exploring whether these classes of disorders have overlapping genetic risk. Overall, genetic factors contribute to individual differences in liability to multiple EDs and SUDs. Although initial family studies concluded that no shared familial (which includes genetic) risk between EDs and SUDs exists, twin studies suggest a moderate proportion of shared variance is attributable to overlapping genetic factors, particularly for those EDs characterized by binge eating and/or inappropriate compensatory behaviours. No adoption or molecular genetic studies have examined shared genetic risk between these classes of disorders. Research investigating binge eating and inappropriate compensatory behaviours using emerging statistical genetic methods, as well as examining gene-environment interplay, will provide important clues into the aetiology of comorbid EDs and SUDs.

Biometric Modeling of Gene-Environment Interplay: The Intersection of Theory and Method and Applications for Social Inequality.

For more than a decade, biometric moderation models have been used to examine whether genetic and environmental influences on individual differences might vary within the population. These quantitative Gene × Environment interaction models have the potential to elucidate not only when genetic and environmental influences on a phenotype might differ, but also why, as they provide an empirical test of several theoretical paradigms that serve as useful heuristics to explain etiology-diathesis-stress, bioecological, differential susceptibility, and social control. In the current article, we review how these developmental theories align with different patterns of findings from statistical models of gene-environment interplay. We then describe the extant empirical evidence, using work by our own research group and others, to lay out genetically informative plausible accounts of how phenotypes related to social inequality-physical health and cognition-might relate to these theoretical models.

Gene-Environment Interplay in Physical, Psychological, and Cognitive Domains in Mid to Late Adulthood: Is APOE a Variability Gene?

Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.

Assessing the salience of gene–environment interplay in the development of anger, family conflict, and physical violence: A biosocial test of General Strain Theory

PurposeAgnew (2014) has recently called for future research on General Strain Theory (GST) to focus on examining the interplay between genetic and environmental factors in order to more accurately understand the developmental origins of antisocial behavior. The current study aimed to answer this call by using kinship pair data from a longitudinal population-based sample. MethodsBehavioral genetic methods were used to assess gene–environment interplay between anger, family conflict, and violence using a subsample of kinship pairs drawn from the Child and Young Adult Supplement of the National Longitudinal Survey of Youth. ResultsResults revealed a significant shared genetic liability for anger and exposure to family conflict indicating gene–environment correlation (rGE). After controlling for rGE, nonshared environmental effects on anger were found to be stronger at higher levels of family conflict implying that family conflict experiences unique to each sibling were involved in creating individual differences in anger. Results also suggested that genetic and nonshared environmental effects accounted for the longitudinal association between anger and physical violence. ConclusionsFindings from the current study underscore the importance of using genetically informed methodologies to identify underlying risk factors involved in both exposure and response to different forms of strain.

Developmental psychopathology, ontogenic process models, gene-environment interplay, and brain development: An emerging synthesis.

This article introduces the special section of the Journal of Abnormal Psychology. This Special Section exemplifies what are arguably the most current iterations of developmental psychopathology, which involve an intensive focus on both molecular genetics and brain architecture-and their interactions with crucial environmental features and forces-for elucidating processes of individual development, or ontogenesis, toward psychopathology.

Aggression in children: unravelling the interplay of genes and environment through (epi)genetics and metabolomics

Aggression inflicts a huge burden on affected children, their families, and society. Estimates for the prevalence of clinical aggression in children range between 2 and 16%, and childhood aggression tends to continue into adulthood. Current psychological treatments and pharmacological interventions are not effective for all children with aggressive behaviors and there is a huge need for more personalized approaches, which requires insight into the heterogeneity and the mechanisms underlying aggression and its associated comorbidities. Here we discuss what is currently known with regard to individual differences in childhood aggression. Studies employing new opportunities in large scale genotyping, epigenetics and metabolomics technology will in future help to explain heterogeneity and highlight pathways from molecule to phenotype. The FP7-ACTION project (Aggression in Children: Unravelling gene-environment interplay to inform Treatment and InterventiON strategies) aims to contribute to knowledge that will help children, their families, teachers and society at large. Proceedings of the 11th International Workshop on Neonatology and Satellite Meetings · Cagliari (Italy) · October 26th-31st, 2015 · From the womb to the adultGuest Editors: Vassilios Fanos (Cagliari, Italy), Michele Mussap (Genoa, Italy), Antonio Del Vecchio (Bari, Italy), Bo Sun (Shanghai, China), Dorret I. Boomsma (Amsterdam, the Netherlands), Gavino Faa (Cagliari, Italy), Antonio Giordano (Philadelphia, USA)

Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

Gene-Environment Interplay and Substance Use: A Review of Recent Findings

Substance use problems are chronic and common public health problems. We review recent studies that implicate genetic and environmental factors in their etiology. Although findings are mixed with respect to specific genotypes, some patterns are evident. For example, exposure to peers or parents who engage in high rates of substance use tends to exacerbate genetic diatheses or eliminate the protective effects of certain genotypes. We discuss reasons for mixed findings and highlight the need for translational research to advance understanding of gene function as well as new methods for using genome-wide data in biologically relevant pathways.

Rodent models for resolving extremes of exercise and health.

The extremes of exercise capacity and health are considered a complex interplay between genes and the environment. In general, the study of animal models has proven critical for deep mechanistic exploration that provides guidance for focused and hypothesis-driven discovery in humans. Hypotheses underlying molecular mechanisms of disease and gene/tissue function can be tested in rodents to generate sufficient evidence to resolve and progress our understanding of human biology. Here we provide examples of three alternative uses of rodent models that have been applied successfully to advance knowledge that bridges our understanding of the connection between exercise capacity and health status. First we review the strong association between exercise capacity and all-cause morbidity and mortality in humans through artificial selection on low and high exercise performance in the rat and the consequent generation of the "energy transfer hypothesis." Second we review specific transgenic and knockout mouse models that replicate the human disease condition and performance. This includes human glycogen storage diseases (McArdle and Pompe) and α-actinin-3 deficiency. Together these rodent models provide an overview of the advancements of molecular knowledge required for clinical translation. Continued study of these models in conjunction with human association studies will be critical to resolving the complex gene-environment interplay linking exercise capacity, health, and disease.

Status Attainment and Social Mobility

This paper discusses why and how the consideration of inter-individual genetic variation can enhance the explanatory power of sociological inquiries of status attainment and social stratification. We argue that accounting for genetic variation may help to address longstanding and in some cases overlooked causality problems in explaining the emergence of social inequalities—problems which may interfere with both implicit and explicit interpretations of a society as “open” or “closed,” as meritocratic or non-meritocratic. We discuss the basic methodological tenets of genetically informative research (Sect. 2) and provide empirical examples and theoretical conceptualizations on how genetic variation contributes to status attainment (Sect. 3). This is followed by a discussion of gene-environment interplay in relation to more abstract ideas about social mechanisms that generate inequality, touching on normative implications of these ideas as well as considerations from a social justice perspective (Sect. 4). Finally, we briefly review the potential benefits as well as pitfalls of incorporating genetic influences into sociological explanations of status attainment. As we will argue, understanding how social influences impinge on the individual and how genes influence our lives requires sophisticated research designs based on sound sociological theory and methodology (Sect. 5).

G×E Interaction Influences Trajectories of Hand Grip Strength.

Age-related decline in grip strength predicts later life disability, frailty, lower well-being and cognitive change. While grip strength is heritable, genetic influence on change in grip strength has been relatively ignored, with non-shared environmental influence identified as the primary contributor in a single longitudinal study. The extent to which gene-environment interplay, particularly gene-environment interactions, contributes to grip trajectories has yet to be examined. We considered longitudinal grip strength measurements in seven twin studies of aging in the Interplay of Genes and Environment across Multiple Studies consortium. Growth curve parameters were estimated for same-sex pairs, aged 34-99 (N=10,681). Fisher's test for mixture distribution of within-monozygotic twin-pair differences (N=1724) was performed on growth curve parameters. We observed significant gene-environment interaction on grip strength trajectories. Finally, we compared the variability of within-pair differences of growth curve parameters by APOE haplotypes. Though not statistically significant, the results suggested that APOE ɛ2ɛ2/ɛ2ɛ3 haplotypes might buffer environmental influences on grip strength trajectories.

Treatment of Child Abuse: Common Ground for Mental Health, Medical, and Legal Practitioners (2nd Edition) edited by R. M.Reece, R. F.Hanson and J.Sargent, John Hopkins University Press, Baltimore, 2014. 392pp. ISBN 978-1-4214-1273-3 (Pbk), £42.00

The book is thoughtfully divided into easy-to-navigate sections. The chapters are organised well and the language used makes it accessible. It begins with succinct, but thoroughly adequate information on the practical aspects of identification, reporting and referral. Of particular quality is the subsequent chapter addressing psychosocial assessment, including a helpful section on associated post-traumatic stress disorder symptoms that may mimic other mental health conditions. ‘Succinct, but thoroughly adequate information on the practical aspects of identification, reporting and referral’ The book addresses evidence-based treatments including trauma-focused cognitive behavioural therapy and parent-child interaction therapy. Importantly, there are chapters on interventions for families, schools and foster carers. The theory, evidence base, advantages and limitations are all explored in great detail. The book also covers medical treatment, both short and long term for sexual and physical abuse, neglect and maltreatment. It looks at the role and training of paediatricians and the role of child abuse paediatricians. The chapter on the importance of therapist and family engagement was particularly strong, and much of the content was also relevant to child and adolescent psychiatry. I found the chapters on gene-environment interplay and resilience particularly interesting, although they were the most complex and least accessible. The book ends on a short chapter regarding legal implications which appeared sufficient for a clinician, but not necessarily a legal practitioner. Of note is the fact that this book is American based, and therefore occasionally is not relevant to UK practice. Overall, however, this book provides a comprehensive look at child abuse. It is well organised, covering most aspects in a clear, easy-to-read format. The range and depth covered are a remarkable achievement and one could see its usefulness in any setting where abused children are considered. ‘The range and depth covered are a remarkable achievement’

Causal effects on child language development: A review of studies in communication sciences and disorders

We reviewed recent studies published across key journals within the field of communication sciences and disorders (CSD) to survey what causal influences on child language development were being considered. Specifically, we reviewed a total of 2921 abstracts published within the following journals between 2003 and 2013: Language, Speech, and Hearing Services in Schools (LSHSS); American Journal of Speech–Language Pathology (AJSLP); Journal of Speech, Language, and Hearing Research (JSLHR); Journal of Communication Disorders (JCD); and the International Journal of Language and Communication Disorders (IJLCD). Of the 346 eligible articles that addressed causal factors on child language development across the five journals, 11% were categorized as Genetic (37/346), 83% (287/346) were categorized as Environmental, and 6% (22/346) were categorized as Mixed. The bulk of studies addressing environmental influences focused on therapist intervention (154/296=52%), family/caregiver linguistic input (65/296=22%), or family/caregiver qualities (39/296=13%). A more in-depth review of all eligible studies published in 2013 (n=34) revealed that family/caregiver qualities served as the most commonly controlled environmental factor (e.g., SES) and only 3 studies explicitly noted the possibility of gene–environment interplay. This review highlighted the need to expand the research base for the field of CSD to include a broader range of environmental influences on child language development (e.g., diet, toxin exposure, stress) and to consider more directly the complex and dynamic interplay between genetic and environmental effects. Learning outcomes: Readers will be able to highlight causal factors on child language development that have been studied over the past decade in CSD and recognize additional influences worthy of consideration. In addition, readers will become familiar with basic tenets of developmental systems theory, including the complex interplay between genetic and environmental factors that shapes child development.

Intergenerational transmission of self-regulation: A multidisciplinary review and integrative conceptual framework.

This review examines mechanisms contributing to the intergenerational transmission of self-regulation. To provide an integrated account of how self-regulation is transmitted across generations, we draw from over 75 years of accumulated evidence, spanning case studies to experimental approaches, in literatures covering developmental, social, and clinical psychology, and criminology, physiology, genetics, and human and animal neuroscience (among others). First, we present a taxonomy of what self-regulation is and then examine how it develops--overviews that guide the main foci of the review. Next, studies supporting an association between parent and child self-regulation are reviewed. Subsequently, literature that considers potential social mechanisms of transmission, specifically parenting behavior, interparental (i.e., marital) relationship behaviors, and broader rearing influences (e.g., household chaos) is considered. Finally, evidence that prenatal programming may be the starting point of the intergenerational transmission of self-regulation is covered, along with key findings from the behavioral and molecular genetics literatures. To integrate these literatures, we introduce the self-regulation intergenerational transmission model, a framework that brings together prenatal, social/contextual, and neurobiological mechanisms (spanning endocrine, neural, and genetic levels, including gene-environment interplay and epigenetic processes) to explain the intergenerational transmission of self-regulation. This model also incorporates potential transactional processes between generations (e.g., children's self-regulation and parent-child interaction dynamics that may affect parents' self-regulation) that further influence intergenerational processes. In pointing the way forward, we note key future directions and ways to address limitations in existing work throughout the review and in closing. We also conclude by noting several implications for intervention work.

Some of the complexities involved in gene-environment interplay.

Tabery’s review of the history of disputes over geneenvironment (G x E) interaction provides a splendid, and persuasive, account of the need to consider the fundamental, philosophical differences between a variationpartitioning approach and a mechanism-elucidation approach—the former being exemplified by Fisher and the latter by Hogben. Fisher is rightly described as a giant of 20th century science but, in relation to G x E, it is relevant that his understanding of some aspects of genetics was poor. This is well exemplified by his attack on the claims from Richard Doll that smoking might cause lung cancer. 1 This was based on the factual evidence that there is a substantial heritability to the propensity to smoke cigarettes. Fisher’s mistake was to ignore the fact that the argument that there was no environmental effect of smoking on cancer had to be based on evidence that the liability to smoking was highly correlated with the liability for lung cancer, and this was neither tested nor shown. Tabery says that Hogben was not so well known as Fisher, although he made an equally lasting contribution to science. It is probably true that Fisher was better known among scientists but it is probably equally true that Hogben was better known to the general public. His book published in 1936 Mathematics for the Million was a wonderful example of how the magic of mathematics could be made both understandable and of riveting interest. 2 Albert Einstein

Genetic and Environmental Influences on Adult Mental Health: Evidence for Gene-Environment Interplay as a Function of Maternal and Paternal Discipline and Affection.

Researchers have long theorized that genetic influence on mental health may differ as a function of environmental risk factors. One likely moderator of genetic and environmental influences on psychopathological symptoms is parenting behavior, as phenotypic research shows that negative aspects of parent-child relationships are associated with greater likelihood of mental illness in adulthood. The current study examined whether levels of reported parental discipline and affection experienced in childhood act as a trigger, or buffer, for adult mental health problems. Results from a nationwide twin sample suggest level of father's discipline and affection, as reported by now-adult twins, moderated genetic and environmental influences on internalizing symptoms in adulthood, such that heritability was greatest at the highest levels of discipline and affection. Father's affection also moderated the etiological influences on alcohol use problems, with greater heritability at the lowest levels of affection. No moderating effect was found for mothers. Findings suggest relationships with fathers in childhood can have long-lasting effects on the etiological influences on adult mental health outcomes.

When chocolate seeking becomes compulsion: gene-environment interplay.

BackgroundEating disorders appear to be caused by a complex interaction between environmental and genetic factors, and compulsive eating in response to adverse circumstances characterizes many eating disorders.Materials and MethodsWe compared compulsion-like eating in the form of conditioned suppression of palatable food-seeking in adverse situations in stressed C57BL/6J and DBA/2J mice, two well-characterized inbred strains, to determine the influence of gene-environment interplay on this behavioral phenotype. Moreover, we tested the hypothesis that low accumbal D2 receptor (R) availability is a genetic risk factor of food compulsion-like behavior and that environmental conditions that induce compulsive eating alter D2R expression in the striatum. To this end, we measured D1R and D2R expression in the striatum and D1R, D2R and α1R levels in the medial prefrontal cortex, respectively, by western blot.ResultsExposure to environmental conditions induces compulsion-like eating behavior, depending on genetic background. This behavioral pattern is linked to decreased availability of accumbal D2R. Moreover, exposure to certain environmental conditions upregulates D2R and downregulates α1R in the striatum and medial prefrontal cortex, respectively, of compulsive animals. These findings confirm the function of gene-environment interplay in the manifestation of compulsive eating and support the hypothesis that low accumbal D2R availability is a “constitutive” genetic risk factor for compulsion-like eating behavior. Finally, D2R upregulation and α1R downregulation in the striatum and medial prefrontal cortex, respectively, are potential neuroadaptive responses that parallel the shift from motivated to compulsive eating.

Gene-Environment Interplay: Where We Are, Where We Are Going.

The idea that both genetic and environmental influences contribute to behavioral outcomes is widely accepted. However, the practice of examining candidate Gene × Environment interaction (cGxE) is controversial. In this article, we summarize some of the key issues involved in cGxE research and provide recommendations for work in this area. Highlighted challenges include the selection of the gene, the development of the cGxE hypothesis, and the coding of the genotype. To address these challenges and gain confidence in cGxE findings, we recommend using empirical data to select and code genes/variants, using theory to develop cGxE hypotheses and a rigorous and transparent approach to hypothesis testing. Family researchers have much to offer to the study of Gene × Environment research in view of their process-oriented theories that are grounded in decades of nuanced measurement of the environment; implementing these best practices will help deliver on that promise.